Updated on 2025/07/31

写真a

 
KAKUTA Hiroki
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Associate Professor
Position
Associate Professor
Homepage
http://www.cc.okayama-u.ac.jp/~kakuta-h/kakuta_lab_english/index.html
External link

Degree

  • 博士（薬学） ( 東京大学 )

  • Ph.D.

Research Interests

  • antitumor drug

  • differentiation inducer

  • retinoids

  • Medicinal chemistry

  • 潰瘍性大腸炎

  • Boron Neutron Capture Therapy

  • 希少疾病

  • 鎮痛

  • 抗アレルギー

  • 抗炎症

  • アラキドン酸カスケード

  • 核内受容体

  • 脂質代謝制御物質創製

  • physiologically active substance

  • nucear receptor

  • anti-inflammatory drug

  • 核内受容体

Research Areas

  • Life Science / Pharmaceutical chemistry and drug development sciences

Education

  • The University of Tokyo   薬学系研究科  

    - 2003

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    Country： Japan

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  • The University of Tokyo   薬学系研究科   分子薬学専攻

    - 2003

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    Country： Japan

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  • The University of Tokyo    

    - 2003

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  • Okayama University    

    - 1997

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  • Okayama University   薬学部   製薬科学科

    - 1997

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    Country： Japan

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Research History

  • The Open University of Japan

    2021.4

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  • Okayama University   Medicine, Dentistry and Pharmaceutical Sciences, Institute of Academic and Research   Associate Professor

    2021.4

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  • Okayama University   Graduate school of Medicine, Dentistry and Pharmaceutical Sciences   Associate Professor

    2008.10 - 2021.3

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  • - Associate Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2008

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  • Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2007 - 2008

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  • 岡山大学医歯薬学総合研究科 助教

    2007 - 2008

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  • Research Associate,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2004 - 2007

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  • 岡山大学医歯薬学総合研究科 助手

    2004 - 2007

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  • Okayama University   Faculty of Pharmaceutical Sciences

    2003 - 2004

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  • Research Associate,Faculty of Pharmaceutical Sciences,Okayama University

    2003 - 2004

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Professional Memberships

Committee Memberships

  • 日本ビタミン学会   幹事  

    2020.6   

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  • 日本ビタミン学会   代議員  

    2018.6   

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    Committee type：Academic society

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  • 日本ビタミン学会   トピックス編集委員  

    2014   

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    Committee type：Academic society

    日本ビタミン学会

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Papers

  • Structural basis for the full and partial agonist activities of retinoid X receptor α ligands with an iso-butoxy and an isopropyl group. Reviewed International journal

    Daisuke Imai, Nobutaka Numoto, Hiroaki Tokiwa, Hiroki Kakuta, Nobutoshi Ito

    Biochemical and biophysical research communications   734   150617 - 150617   2024.11

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    Language：English   Publishing type：Research paper (scientific journal)  

    Retinoid X receptors (RXRs) belong to a retinoid-binding subgroup of the nuclear receptor family, and their synthetic agonists have been developed as therapeutics for glucose and lipid metabolism, inflammation, and inflammatory bowel disease, although RXR agonists could cause side effects such as hypothyroidism, hypertriglyceridemia, and hepatomegaly. We previously reported novel full and partial agonists, NEt-3IB and NEt-4IB, which reduce the side effects, but the molecular basis of their different activity was not clear. In this study, we report the crystal structures of the ligand-binding domain of human RXRα complexed with NEt-3IB and NEt-4IB. Detailed comparisons of the two structures showed that the full agonist, NEt-3IB, is more stably accommodated in the ligand-binding pocket due to the interactions of the bulky iso-butoxy group with helices 5 and 7. The stabilization of these helices led to the stabilization of helix 12, which is important for formation of the coactivator-binding site. The structures shed light on the novel mechanism of the regulation of RXR activity through the interaction between the bound agonist and helix 7, an interaction that was not previously considered important.

    DOI： 10.1016/j.bbrc.2024.150617

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  • Simple Fluorescence Labeling Method Enables Detection of Intracellular Distribution and Expression Level of Retinoid X Receptors Reviewed

    Yukina Tanaka, Michiko Fujihara, Yuta Takamura, Mayu Kawasaki, Shogo Nakano, Makoto Makishima, Hiroki Kakuta

    ACS Medicinal Chemistry Letters   2024.5

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

    DOI： 10.1021/acsmedchemlett.4c00033

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  • Direct evaluation of polarity of the ligand binding pocket in retinoid X receptor using a fluorescent solvatochromic agonist. Reviewed International journal

    Kizuku Miura, Michiko Fujihara, Masaki Watanabe, Yuta Takamura, Mayu Kawasaki, Shogo Nakano, Hiroki Kakuta

    Bioorganic & medicinal chemistry letters   96   129536 - 129536   2023.10

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    High selectivity of small-molecule drug candidates for their target molecule is important to minimize potential side effects. One factor that contributes to the selectivity is the internal polarity of the ligand-binding pocket (LBP) in the target molecule, but this is difficult to measure. Here, we first confirmed that the retinoid X receptor (RXR) agonist 6-(ethyl(1-isobutyl-2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)amino)nicotinic acid (NEt-iFQ, 1) exhibits fluorescence solvatochromism, i.e., its Stokes shift depends on the polarity of the solvent, and then we utilized this property to directly measure the internal polarity of the RXRα-LBP. The Stokes shift of 1 when bound to the RXRα-LBP corresponded to that of 1 in chloroform solution. This finding is expected to be helpful for designing RXR-selective ligands. A similar approach should be appliable to evaluate the internal polarity of the LBPs of other receptors.

    DOI： 10.1016/j.bmcl.2023.129536

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  • Ligand Screening System for the RXRα Heterodimer Using the Fluorescence RXR Agonist CU-6PMN Reviewed

    Mayu Kawasaki, Tomoharu Motoyama, Shoya Yamada, Masaki Watanabe, Michiko Fujihara, Akira Kambe, Shogo Nakano, Hiroki Kakuta, Sohei Ito

    ACS Medicinal Chemistry Letters   14 ( 3 )   291 - 296   2023.2

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acsmedchemlett.2c00509

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  • Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha. Reviewed International journal

    Susumu Kodama, Shuzo Matsumoto, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Atsushi Ono, Hiroki Kakuta

    Toxicology letters   373   76 - 83   2022.11

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    Language：English   Publishing type：Research paper (scientific journal)  

    Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

    DOI： 10.1016/j.toxlet.2022.11.003

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  • Analysis of absorption-enhancing mechanisms for combinatorial use of spermine with sodium taurocholate in Caco-2 cells. Reviewed International journal

    Masato Maruyama, Yohei Nishida, Hironori Tanaka, Takako Minami, Ken-Ichi Ogawara, Masateru Miyake, Yuta Takamura, Hiroki Kakuta, Kazutaka Higaki

    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V   180   332 - 343   2022.11

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    Language：English   Publishing type：Research paper (scientific journal)  

    Previously, we reported that the combined use of spermine (SPM) and sodium taurocholate (STC) (SPM-STC) significantly improves the oral absorption of rebamipide (BCS class IV) and pulmonary absorption of interferon-α without any harmful histopathological changes in the gastrointestinal tract and lungs, respectively. In the present study, we examined the effect of SPM-STC on the transport of fluorescein isothiocyanate-labeled dextrans (FDs) across Caco-2 cell monolayers and attempted to clarify the mechanisms underlying the transport enhancement caused by SPM-STC. SPM-STC were found to significantly enhance the transport of FDs, while the treatment with SPM-STC was not harmful, and the decrease in transepithelial electrical resistance was transient and reversible. The voltage-clamp study clearly indicated that the opening of the paracellular route could be mainly responsible for the enhanced transport of FD-4. As for the mechanisms, it was found that SPM-STC caused a significant increase in membrane fluidity, which would lead to the enhanced transport of small-molecule drugs such as rebamipide. Since SPM-STC increased intracellular Ca2+ via Ca2+ uptake through Ca2+ channels and Ca2+ release from the endoplasmic reticulum stimulated by the IP3 pathway, the subsequent possible activation of the MLCK signaling pathway would have led to the contraction of the actin-myosin ring. The rearrangement of tight junction-constituting proteins induced through the MAPK pathway has also been suggested as a possible mechanism for opening tight junctions. Claudin-4, a key protein constituting the tight junction, merged with F-actin along with the plasma membrane, was significantly decreased, which would be at least partial structural evidence for the tight-junction opening.

    DOI： 10.1016/j.ejpb.2022.10.020

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  • Teratogenicity and Fetal-Transfer Assessment of the Retinoid X Receptor Agonist Bexarotene. Reviewed International journal

    Yuta Takamura, Izumi Kato, Manami Fujita-Takahashi, Midori Azuma-Nishii, Masaki Watanabe, Rui Nozaki, Masaru Akehi, Takanori Sasaki, Hiroyuki Hirano, Hiroki Kakuta

    ACS pharmacology & translational science   5 ( 9 )   811 - 818   2022.9

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [11C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.

    DOI： 10.1021/acsptsci.2c00126

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  • Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo. Reviewed International journal

    Negar Khazan, Kyu Kwang Kim, Jeanne N Hansen, Niloy A Singh, Taylor Moore, Cameron W A Snyder, Ravina Pandita, Myla Strawderman, Michiko Fujihara, Yuta Takamura, Ye Jian, Nicholas Battaglia, Naohiro Yano, Yuki Teramoto, Leggy A Arnold, Russell Hopson, Keshav Kishor, Sneha Nayak, Debasmita Ojha, Ashoke Sharon, John M Ashton, Jian Wang, Michael T Milano, Hiroshi Miyamoto, David C Linehan, Scott A Gerber, Nada Kawar, Ajay P Singh, Erdem D Tabdanov, Nikolay V Dokholyan, Hiroki Kakuta, Peter W Jurutka, Nina F Schor, Rachael B Rowswell-Turner, Rakesh K Singh, Richard G Moore

    Journal of Medicinal Chemistry   65 ( 8 )   6039 - 6055   2022.4

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize.

    DOI： 10.1021/acs.jmedchem.1c01878

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  • Increased Molecular Flexibility Widens the Gap between Ki and Kd values in Screening for Retinoid X Receptor Modulators Reviewed

    Masaki Watanabe, Mariko Nakamura-Nakayama, Michiko Fujihara, Mayu Kawasaki, Shogo Nakano, Hiroki Kakuta

    ACS Medicinal Chemistry Letters   13 ( 2 )   211 - 217   2022.1

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acsmedchemlett.1c00575

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  • A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice Reviewed International journal

    Ryohtaroh Matsumoto, Daisuke Takahashi, Masaki Watanabe, Shunsuke Nakatani, Yuta Takamura, Yuji Kurosaki, Hiroki Kakuta, Koji Hase

    Frontiers in Pharmacology   12   715752   2021.8

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RB<sup>high</sup>CD4<sup>+</sup> T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

    DOI： 10.3389/fphar.2021.715752

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  • Creation of Fluorescent RXR Antagonists Based on CBTF-EE and Application to a Fluorescence Polarization Binding Assay Reviewed

    Maho Takioku, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Shoya Yamada, Mayu Kawasaki, Sohei Ito, Shogo Nakano, Hiroki Kakuta

    ACS Medicinal Chemistry Letters   2021.6

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

    DOI： 10.1021/acsmedchemlett.1c00201

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  • In Vivo Receptor Visualization and Evaluation of Receptor Occupancy with Positron Emission Tomography Invited Reviewed

    Yuta Takamura, Hiroki Kakuta

    Journal of Medicinal Chemistry   64 ( 9 )   5226 - 5251   2021.5

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

    DOI： 10.1021/acs.jmedchem.0c01714

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  • Discovery of a “Gatekeeper” Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers Reviewed

    Masaki Watanabe, Michiko Fujihara, Tomoharu Motoyama, Mayu Kawasaki, Shoya Yamada, Yuta Takamura, Sohei Ito, Makoto Makishima, Shogo Nakano, Hiroki Kakuta

    Journal of Medicinal Chemistry   64 ( 1 )   430 - 439   2021.1

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

    DOI： 10.1021/acs.jmedchem.0c01354

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  • Fluorescence properties of retinoid X receptor antagonist NEt-SB Reviewed

    Shoya Yamada, Yuta Takamura, Michiko Fujihara, Mayu Kawasaki, Sohei Ito, Shogo Nakano, Hiroki Kakuta

    Bioorganic & Medicinal Chemistry Letters   31   127666 - 127666   2021.1

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

    DOI： 10.1016/j.bmcl.2020.127666

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  • A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice. Reviewed International journal

    Ryohtaroh Matsumoto, Daisuke Takahashi, Masaki Watanabe, Shunsuke Nakatani, Yuta Takamura, Yuji Kurosaki, Hiroki Kakuta, Koji Hase

    Frontiers in pharmacology   12   715752 - 715752   2021

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

    DOI： 10.3389/fphar.2021.715752

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  • Convenient Retinoid X Receptor Binding Assay Based on Fluorescence Change of the Antagonist NEt-C343. Reviewed

    Hiroki Kakuta

    Journal of Medicinal Chemistry   64 ( 1 )   861 - 870   2020.12

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    Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

    Retinoid X receptor (RXR) modulators (rexinoids) are considered to have therapeutic potential for multiple diseases, such as Alzheimer's disease and Parkinson's disease. To overcome various disadvantages of prior screening methods, we previously developed an RXR binding assay using a fluorescent RXR ligand, CU-6PMN (4). However, this ligand binds not only at the ligand-binding domain (LBD) but also at the dimer-dimer interface of hRXRα. Here, we present a new fluorescent RXR antagonist 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxamido)phenyl)amino]nicotinic acid (NEt-C343, 7), which emits strong fluorescence only when bound to the RXR-LBD. It allows us to perform a rapid, simple, and nonhazardous binding assay that does not require bound/free separation and uses a standard plate reader. The obtained Ki values of known compounds were correlated with the Ki values obtained using the standard [3H]9cis-retinoic acid assay. This assay should be useful for drug discovery as well as for research on endocrine disruptors, functional foods, and natural products.

    DOI： 10.1021/acs.jmedchem.0c01883

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  • Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells Reviewed International journal

    Hend M Nawara, SAID M AFIFY, Ghmkin Hassan, Maram H. Zahra, Marwa Atallah, Hager Mansour, Hagar A. Abu Quora, Md Jahangir Alam, Amira Osman, Hiroki Kakuta, Hiroki Hamada, Akimasa Seno, Masaharu Seno

    Cancers   12 ( 6 )   1360 - 1360   2020.5

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

    "Combination therapy", which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC50 values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 µM, respectively, IC50 of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 µM sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 µM of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 µM sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects.

    DOI： 10.3390/cancers12061360

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  • Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice Reviewed International journal

    Ikuo Kimura, Junki Miyamoto, Ryuji Ohue-Kitano, Keita Watanabe, Takahiro Yamada, Masayoshi Onuki, Ryo Aoki, Yosuke Isobe, Daiji Kashihara, Daisuke Inoue, Akihiko Inaba, Yuta Takamura, Satsuki Taira, Shunsuke Kumaki, Masaki Watanabe, Masato Ito, Fumiyuki Nakagawa, Junichiro Irie, Hiroki Kakuta, Masakazu Shinohara, Ken Iwatsuki, Gozoh Tsujimoto, Hiroaki Ohno, Makoto Arita, Hiroshi Itoh, Koji Hase

    Science   367 ( 6481 )   2020.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    <jats:p>Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.</jats:p>

    DOI： 10.1126/science.aaw8429

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  • Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets Reviewed International journal

    Noriko Itaba, Yohei Kono, Kaori Watanabe, Tsuyoshi Yokobata, Hiroyuki Oka, Mitsuhiko Osaki, Hiroki Kakuta, Minoru Morimoto, Goshi Shiota

    Scientific Reports   9 ( 1 )   6841 - 6841   2019.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

    Chronic hepatitis viral infection, alcoholic intoxication, and obesity cause liver fibrosis, which progresses to decompensated liver cirrhosis, a disease for which medical demands cannot be met. Since there are currently no approved anti-fibrotic therapies for established liver fibrosis, the development of novel modalities is required to improve patient prognosis. In this study, we clarified the anti-fibrotic effects of cell sheets produced from human bone marrow-derived mesenchymal stem cells (MSCs) incubated on a temperature-sensitive culture dish with the chemical compound IC-2. Orthotopic transplantation of IC-2-engineered MSC sheets (IC-2 sheets) remarkably reduced liver fibrosis induced by chronic CCl4 administration. Further, the marked production of fibrolytic enzymes such as matrix metalloproteinase (MMP)-1 and MMP-14, as well as thioredoxin, which suppresses hepatic stellate cell activation, was observed in IC-2 sheets. Moreover, the anti-fibrotic effect of IC-2 sheets was much better than that of MSC sheets. Finally, knockdown experiments revealed that MMP-14 was primarily responsible for the reduction of liver fibrosis. Here, we show that IC-2 sheets could be a promising therapeutic option for established liver fibrosis.

    DOI： 10.1038/s41598-019-43298-0

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  • Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening. Reviewed International journal

    Shoya Yamada, Mayu Kawasaki, Michiko Fujihara, Masaki Watanabe, Yuta Takamura, Maho Takioku, Hiromi Nishioka, Yasuo Takeuchi, Makoto Makishima, Tomoharu Motoyama, Sohei Ito, Hiroaki Tokiwa, Shogo Nakano, Hiroki Kakuta

    Journal of Medicinal Chemistry   62 ( 19 )   8809 - 8818   2019.10

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.

    DOI： 10.1021/acs.jmedchem.9b00995

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  • 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity Reviewed International journal

    Yuta Takamura, Manami Takahashi, Midori Nishii, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Hiroki Kakuta

    Bioorganic & Medicinal Chemistry Letters   29 ( 15 )   1891 - 1894   2019.8

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

    Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.

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  • Fluorine-18 (18F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands Reviewed International journal

    Hiroki Kakuta

    Bioorganic & Medicinal Chemistry   27 ( 14 )   3128 - 3134   2019.5

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    Bexarotene (1), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a 11C-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [11C]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 (18F)-labeled PET tracer [18F]6 derived from RXR partial agonist CBt-PMN (2), which has lower lipophilicity and weaker RXR-binding ability than [11C]1. The concomitant administration of 1 or 2 with [18F]6 with resulted in decreased accumulation of [18F]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [18F]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [18F]6 followed by increased accumulation in other tissues.

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  • Correction to Synthesis of 11C-Labeled RXR Partial Agonist 1-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [11C]Carbon Dioxide Fixation via Organolithiation of Tri Reviewed

    Shibahara O, Watanabe M, Takamura Y, Yamada S, Akehi M, Sasaki T, Akahoshi A, Hanada T, Hirano H, Nakatani S, Nishioka H, Takeuchi Y, Kakuta H

    Journal of Medicinal Chemistry   62 ( 9 )   4780 - 4781   2019.5

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    DOI： 10.1021/acs.jmedchem.9b00617

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  • A partial agonist for retinoid X receptor mitigates experimental colitis. Reviewed International journal

    Masayoshi Onuki, Masaki Watanabe, Narumi Ishihara, Koichiro Suzuki, Kei Takizawa, Masato Hirota, Takahiro Yamada, Aiko Egawa, Osamu Shibahara, Midori Nishii, Michiko Fujihara, Makoto Makishima, Daisuke Takahashi, Yukihiro Furusawa, Hiroki Kakuta, Koji Hase

    International immunology   31 ( 4 )   251 - 262   2019.3

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    Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

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  • 変形性関節症:from bench to bedside 関節軟骨のバイオイメージング

    大橋 俊孝, 加来田 博貴, 大野 充昭, 西田 圭一郎

    日本整形外科学会雑誌   93 ( 2 )   S331 - S331   2019.3

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  • A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. Reviewed International journal

    Daisuke Morichika, Nobuaki Miyahara, Utako Fujii, Akihiko Taniguchi, Naohiro Oda, Satoru Senoo, Mikio Kataoka, Mitsune Tanimoto, Hiroki Kakuta, Katsuyuki Kiura, Yoshinobu Maeda, Arihiko Kanehiro

    Respiratory research   20 ( 1 )   2 - 2   2019.1

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    BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. METHODS: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. RESULTS: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. CONCLUSION: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

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  • Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα) Reviewed International journal

    Yurina Miyashita, Nobutaka Numoto, Sundaram Arulmozhiraja, Shogo Nakano, Naoya Matsuo, Kanade Shimizu, Osamu Shibahara, Michiko Fujihara, Hiroki Kakuta, Sohei Ito, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa

    FEBS Letters   593 ( 2 )   242 - 250   2019.1

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    1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (CBt-PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt-PMN-bound ligand-binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt-PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF-2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt-PMN in the complex is probably the reason behind its partial agonistic activity.

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  • Problems with laboratory notebooks in academia and how to resolve them

    Kakuta, H.

    Yakugaku Zasshi   139 ( 6 )   2019

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    DOI： 10.1248/yakushi.18-00193-3

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  • Towards further sharing of knowledge and activities on standards of quality assurance (Qa) across industry, academia and government to promote research integrity and accelerate drug discovery

    Kakuta, H., Sudo, H.

    Yakugaku Zasshi   139 ( 6 )   2019

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    DOI： 10.1248/yakushi.18-00193-F

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  • Retinoid X Receptor Antagonists

    Masaki Watanabe, Hiroki Kakuta

    International Journal of Molecular Sciences   19 ( 8 )   2354 - 2354   2018.8

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    DOI： 10.3390/ijms19082354

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  • Retinoid X Receptor Antagonists

    Hiroki Kakuta

    International Journal of Molecular Sciences   2018.8

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  • Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer Reviewed International journal

    Rayna Rosati, Lisa Polin, Charles Ducker, Jing Li, Xun Bao, Dakshnamurthy Selvakumar, Seongho Kim, Besa Xhabija, Martha Larsen, Thomas McFall, Yanfang Huang, Benjamin L Kidder, Andrew Fribley, Janice Saxton, Hiroki Kakuta, Peter Shaw, Manohar Ratnam

    Clinical cancer research : an official journal of the American Association for Cancer Research   24 ( 24 )   6509 - 6522   2018

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    PURPOSE: Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity. EXPERIMENTAL DESIGN: Small-molecule drug discovery and extensive biological characterization of a lead compound. RESULTS: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl. CONCLUSIONS: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

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  • Retinoid X receptor antagonists

    Watanabe, M., Kakuta, H.

    International Journal of Molecular Sciences   19 ( 8 )   2018

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    DOI： 10.3390/ijms19082354

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  • Retinoid X Receptor Antagonists

    Hiroki Kakuta

    International journal of molecular sciences   2018

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    DOI： 10.20944/preprints201806.0208.v1

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  • Synthesis of 11C-Labeled RXR Partial Agonist 1-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [11C]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof Reviewed International journal

    Osamu Shibahara, Masaki Watanabe, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Hiroyuki Hirano, Shunsuke Nakatani, Hiromi Nishioka, Yasuo Takeuchi, Hiroki Kakuta

    Journal of Medicinal Chemistry   60 ( 16 )   7139 - 7145   2017.8

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    DOI： 10.1021/acs.jmedchem.7b00817

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  • Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma. Reviewed International journal

    Utako Fujii, Nobuaki Miyahara, Akihiko Taniguchi, Naohiro Oda, Daisuke Morichika, Etsuko Murakami, Hikari Nakayama, Koichi Waseda, Mikio Kataoka, Hiroki Kakuta, Mitsune Tanimoto, Arihiko Kanehiro

    Respiratory research   18 ( 1 )   23 - 23   2017.1

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    BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. METHODS: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. RESULTS: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression. CONCLUSION: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

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  • Effect Of A Retinoid X Receptor Partial Agonist On The Development Of Emphysema And Airway Inflammation In A Murine Model Of Emphysema Reviewed

    D. Morichika, A. Kanehiro, H. Kakuta, A. Taniguchi, U. Fujii, N. Oda, N. Miyahara, K. Kiura, M. Tanimoto

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   195   2017

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  • Retinoid X Receptor Ligands with Anti-Type 2 Diabetic Activity

    Hiroki Kakuta

    Current topics in medicinal chemistry   2017

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    DOI： 10.2174/1568026616666160617085545

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  • Treatment With Novel Retinoid X Receptor Partial Agonist Attenuates Eosinophilic Airway Inflammation And Airway Hyperresponsiveness Reviewed

    U. Fujii, A. Kanehiro, N. Miyahara, N. Oda, D. Morichika, A. Taniguchi, G. Ikeda, H. Nakayama, K. Waseda, E. Murakami, H. Kakuta, M. Kataoka, K. Kiura, M. Tanimoto

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   193   2016

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  • Retinoid x receptor ligands with anti-type 2 diabetic activity

    Morishita, K.-I., Kakuta, H.

    Current Topics in Medicinal Chemistry   16 ( 30 )   2016

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  • RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects Reviewed

    Kohei Kawata, Ken-ichi Morishita, Mariko Nakayama, Shoya Yamada, Toshiki Kobayashi, Yuki Furusawa, Sakae Arimoto-Kobayashi, Toshitaka Oohashi, Makoto Makishima, Hirotaka Naitou, Erika Ishitsubo, Hiroaki Tokiwa, Akihiro Tai, Hiroki Kakuta

    JOURNAL OF MEDICINAL CHEMISTRY   58 ( 2 )   912 - 926   2015.1

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    DOI： 10.1021/jm501863r

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  • Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists Reviewed

    Toshiki Kobayashi, Yuki Furusawa, Shoya Yamada, Masaru Akehi, Fumiaki Takenaka, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Eiji Matsuura, Hiroyuki Hirano, Akihiro Tai, Hiroki Kakuta

    ACS medicinal chemistry letters   6 ( 3 )   334 - 338   2015

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    DOI： 10.1021/ml500511m

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  • Involvement of glucocorticoid receptor activation on anti-inflammatory effect induced by peroxisome proliferator-activated receptor γ agonist in mice Reviewed International journal

    Hiroki Kakuta

    International immunopharmacology   22 ( 1 )   204 - 8   2014

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    DOI： 10.1016/j.intimp.2014.06.028

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  • Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes Reviewed

    Yoshiki Murakami, Yasumasa Shimizu, Akemi Ogasawara, Satoshi Ueshima, Mariko Nakayama, Kohei Kawata, Hiroki Kakuta, Tetsuya Aiba

    Drug development and industrial pharmacy   40 ( 8 )   1065 - 1071   2014

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    DOI： 10.3109/03639045.2013.807278

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  • In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs Reviewed

    Bishoy Y A El-Aarag, Tomonari Kasai, Magdy A H Zahran, Nadia I Zakhary, Tsukasa Shigehiro, Sreeja C Sekhar, Hussein S Agwa, Akifumi Mizutani, Hiroshi Murakami, Hiroki Kakuta, Masaharu Seno

    International immunopharmacology   21 ( 2 )   283 - 292   2014

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    DOI： 10.1016/j.intimp.2014.05.007

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  • Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid and structural development to increase potency Reviewed

    Fuminori Ohsawa, Shoya Yamada, Nobumasa Yakushiji, Ryosuke Shinozaki, Mariko Nakayama, Kohei Kawata, Manabu Hagaya, Toshiki Kobayashi, Kazutaka Kohara, Yuuki Furusawa, Chisa Fujiwara, Yui Ohta, Makoto Makishima, Hirotaka Naitou, Akihiro Tai, Yutaka Yoshikawa, Hiroyuki Yasui, Hiroki Kakuta

    Journal of medicinal chemistry   56 ( 5 )   1865 - 1877   2013

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  • RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists Reviewed

    Hiroki Kakuta, Nobumasa Yakushiji, Ryosuke Shinozaki, Fuminori Ohsawa, Shoya Yamada, Yui Ohta, Kohei Kawata, Mariko Nakayama, Manabu Hagaya, Chisa Fujiwara, Makoto Makishima, Shigeyuki Uno, Akihiro Tai, Ami Maehara, Masaru Nakayama, Toshitaka Oohashi, Hiroyuki Yasui, Yutaka Yoshikawa

    ACS medicinal chemistry letters   3 ( 5 )   427 - 432   2012

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  • Relevance of nuclear receptor expression in a Tchreg cell line, HOZOT: RXRα and PPARγ negatively regulate IFN-γ production Reviewed

    Hiroki Kakuta

    Results in immunology   2   158 - 165   2012

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    DOI： 10.1016/j.rinim.2012.08.001

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  • Feasibility of structural modification of retinoid X receptor agonists to separate blood glucose-lowering action from adverse effects: studies in KKA(y) type 2 diabetes model mice Reviewed

    Hiroki Kakuta, Fuminori Ohsawa, Shoya Yamada, Makoto Makishima, Akihiro Tai, Hiroyuki Yasui, Yutaka Yoshikawa

    Biological & pharmaceutical bulletin   35 ( 4 )   629 - 633   2012

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  • Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor γ Agonist In Vivo Reviewed

    Hiroki Kakuta

    PPAR research   2011   840194   2011

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    DOI： 10.1155/2011/840194

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  • An arylidene-thiazolidinedione derivative, GPU-4, without PPARγ activation, reduces retinal neovascularization Reviewed

    Hiroki Kakuta

    Current neurovascular research   8 ( 1 )   25 - 34   2011

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    DOI： 10.2174/156720211794520224

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  • Design and synthesis of novel cyclooxygenase-1 inhibitors as analgesics: 5-amino-2-ethoxy-N-(substituted-phenyl)benzamides Reviewed

    Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Akihiro Tai, Futoshi Yazama, Hiroki Kakuta

    ChemMedChem   6 ( 3 )   550 - 560   2011

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    DOI： 10.1002/cmdc.201000462

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  • Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats Reviewed

    Akemi Ogasawara, Yoshiki Murakami, Nobumasa Yakushiji, Fuminori Ohsawa, Jun-Ichi Kusaba, Tetsuya Aiba, Yuji Kurosaki, Hiroki Kakuta

    Drug development and industrial pharmacy   37 ( 9 )   1060 - 1067   2011

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    DOI： 10.3109/03639045.2011.559247

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  • Replacement of the hydrophobic part of 9-cis-retinoic acid with cyclic terpenoid moiety results in RXR-selective agonistic activity Reviewed

    Takashi Okitsu, Kana Sato, Kinya Iwatsuka, Natsumi Sawada, Kimie Nakagawa, Toshio Okano, Shoya Yamada, Hiroki Kakuta, Akimori Wada

    Bioorganic & medicinal chemistry   19 ( 9 )   2939 - 2949   2011

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    DOI： 10.1016/j.bmc.2011.03.033

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  • Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB Reviewed

    Mariko Nakayama, Shoya Yamada, Fuminori Ohsawa, Yui Ohta, Kohei Kawata, Makoto Makishima, Hiroki Kakuta

    ACS medicinal chemistry letters   2 ( 12 )   896 - 900   2011

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  • Cyclic-tri(N-methyl-meta-benzamide)s: substituent effects on the bowl-shaped conformation in the crystal and solution states Reviewed

    Hiroki Kakuta, Isao Azumaya, Hyuma Masu, Mio Matsumura, Kentaro Yamaguchi, Hiroyuki Kagechika, Aya Tanatani

    TETRAHEDRON   66 ( 42 )   8254 - 8260   2010.10

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    DOI： 10.1016/j.tet.2010.08.049

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  • Fluorescent retinoid X receptor ligands for fluorescence polarization assay Reviewed

    Yamada S, Ohsawa F, Fujii S, Shinozaki R, Makishima M, Naitou H, Enomoto S, Tai A, Kakuta H.

    Bioorganic & medicinal chemistry letters   20 ( 17 )   5143 - 5146   2010

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    DOI： 10.1016/j.bmcl.2010.07.011

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  • Effect of 5-aminosalicylate on allergic rhinitis model in mice Reviewed

    Shoji Kuyama, Atsuki Yamamoto, Mayu Sugiyama, Hiroki Kakuta, Yukio Sugimoto

    International immunopharmacology   10 ( 6 )   713 - 716   2010

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    DOI： 10.1016/j.intimp.2010.03.007

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  • Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation Reviewed

    Shuji Fujii, Fuminori Ohsawa, Shoya Yamada, Ryosuke Shinozaki, Ryosuke Fukai, Makoto Makishima, Shuichi Enomoto, Akihiro Tai, Hiroki Kakuta

    Bioorganic & medicinal chemistry letters   20 ( 17 )   5139 - 5142   2010

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    DOI： 10.1016/j.bmcl.2010.07.012

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  • Identification of urine metabolites of TFAP, a cyclooxygenase-1 inhibitor Reviewed

    Hiroki Kakuta, Ryosuke Fukai, Zheng Xiaoxia, Fuminori Ohsawa, Takeshi Bamba, Kazumasa Hirata, Akihiro Tai

    Bioorganic & medicinal chemistry letters   20 ( 6 )   1840 - 1843   2010

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    DOI： 10.1016/j.bmcl.2010.01.161

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  • Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers Reviewed

    Fuminori Ohsawa, Ken-Ichi Morishita, Shoya Yamada, Makoto Makishima, Hiroki Kakuta

    ACS medicinal chemistry letters   1 ( 9 )   521 - 525   2010

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    DOI： 10.1021/ml100184k

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  • Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity Reviewed

    Ken-ichi Morishita, Nobumasa Yakushiji, Fuminori Ohsawa, Kayo Takamatsu, Nobuyasu Matsuura, Makoto Makishima, Masatoshi Kawahata, Kentaro Yamaguchi, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

    Bioorganic & medicinal chemistry letters   19 ( 3 )   1001 - 1003   2009

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    DOI： 10.1016/j.bmcl.2008.11.086

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  • Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation Reviewed

    Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

    Journal of pharmaceutical sciences   97 ( 12 )   5446 - 5452   2008

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    DOI： 10.1002/jps.21388

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  • Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus Reviewed

    Kensuke Namba, Xiaoxia Zheng, Kazunori Motoshima, Hidetomo Kobayashi, Akihiro Tai, Eizo Takahashi, Kenji Sasaki, Keinosuke Okamoto, Hiroki Kakuta

    Bioorganic & medicinal chemistry   16 ( 11 )   6131 - 6144   2008

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    DOI： 10.1016/j.bmc.2008.04.040

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  • Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRalpha-preferential agonist possessing a sulfonamide moiety Reviewed

    Hiroki Kakuta

    ChemMedChem   3 ( 3 )   454 - 460   2008

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    DOI： 10.1002/cmdc.200700265

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  • Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor Reviewed

    Hiroki Kakuta, Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Kenji Sasaki, Akihiro Tai

    Journal of medicinal chemistry   51 ( 8 )   2400 - 2411   2008

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    DOI： 10.1021/jm701191z

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  • The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist) Reviewed

    Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Kazunori Morohashi, Ken-ichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

    ChemMedChem   3 ( 5 )   780 - 787   2008

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    DOI： 10.1002/cmdc.200700313

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  • Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum Reviewed

    Mai Yoshikawa, Kazunori Motoshima, Kanji Fujimoto, Akihiro Tai, Hiroki Kakuta, Kenji Sasaki

    Bioorganic & medicinal chemistry   16 ( 11 )   6027 - 6033   2008

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    DOI： 10.1016/j.bmc.2008.04.051

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  • Necessity is the mother of invention: an ingenious method for leukocyte-targeted delivery of siRNA in stabilized nanoparticles demonstrates a role of cyclin D1 in inflammation

    Hiroki Kakuta

    ChemMedChem   2008

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    DOI： 10.1002/cmdc.200800095

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  • Necessity is the mother of invention: An ingenious method for leukocyte-targeted delivery of siRNA in stabilized nanoparticles demonstrates a role of cyclin D1 in inflammation

    Kakuta, H.

    ChemMedChem   3 ( 7 )   2008

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    DOI： 10.1002/cmdc.200800095

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  • Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors (vol 15, pg 1014, 2007) Reviewed

    Xiaoxia Zheng, Hiroyuki Oda, Kayo Takamatsu, Yukio Sugimoto, Akihiro Tai, Eiichi Akaho, Hamed Ismail Ali, Toshiyuki Oshiki, Hiroki Kakuta, Kenji Sasaki

    BIOORGANIC & MEDICINAL CHEMISTRY   15 ( 9 )   3299 - 3300   2007.5

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    DOI： 10.1016/j.bmc.2007.01.059

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  • Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors Reviewed

    Xiaoxia Zheng, Hiroyuki Oda, Kayo Takamatsu, Yukio Sugimoto, Akihiro Tai, Eiichi Akaho, Hamed Ismail Ali, Toshiyuki Oshiki, Hiroki Kakuta, Kenji Sasaki

    Bioorganic & medicinal chemistry   15 ( 2 )   1014 - 1021   2007

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    DOI： 10.1016/j.bmc.2006.10.029

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  • Antimalarial cation-dimers synthesized in two steps from an inexpensive starting material, isonicotinic acid Reviewed

    Kazunori Motoshima, Yoshiko Hiwasa, Mai Yoshikawa, Kanji Fujimoto, Akihiro Tai, Hiroki Kakuta, Kenji Sasaki

    ChemMedChem   2 ( 10 )   1527 - 1532   2007

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    DOI： 10.1002/cmdc.200700107

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  • Antimalarial effect of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide) Reviewed

    Kanji Fujimoto, Daiki Morisaki, Munehiro Yoshida, Tetsuto Namba, Kim Hye-Sook, Yusuke Wataya, Hiroki Kourai, Hiroki Kakuta, Kenji Sasaki

    Bioorganic & medicinal chemistry letters   16 ( 10 )   2758 - 2760   2006

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    DOI： 10.1016/j.bmcl.2006.02.030

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  • Membrane permeabilization by non-steroidal anti-inflammatory drugs Reviewed

    Tomisato W, Tanaka K, Katsu T, Kakuta H, Sasaki K, Tsutsumi S, Hoshino T, Aburaya M, Li D, Tsuchiya T, Suzuki K, Yokomizo K, Mizushima T.

    Biochemical and biophysical research communications   323 ( 3 )   1032 - 1039   2004

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    DOI： 10.1016/j.bbrc.2004.08.205

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  • Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton Reviewed

    Hiroki Kakuta, Aya Tanatani, Kazuo Nagasawa, Yuichi Hashimoto

    Chemical & pharmaceutical bulletin   51 ( 11 )   1273 - 1282   2003

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    DOI： 10.1248/cpb.51.1273

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  • Cyclooxygenase inhibitors derived from thalidomide Reviewed

    Mamiko Suizu, Yohei Muroya, Hiroki Kakuta, Hiroyuki Kagechika, Aya Tanatani, Kazuo Nagasawa, Yuichi Hashimoto

    Chemical & pharmaceutical bulletin   51 ( 9 )   1098 - 1102   2003

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    DOI： 10.1248/cpb.51.1098

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  • Fluorescent bioprobes for visualization of puromycin-sensitive aminopeptidase in living cells Reviewed

    Hiroki Kakuta, Yukiko Koiso, Kazuo Nagasawa, Yuichi Hashimoto

    Bioorganic & medicinal chemistry letters   13 ( 1 )   83 - 86   2003

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/s0960-894x(02)00845-4

    DOI： 10.1016/S0960-894X(02)00845-4

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  • Specific inhibitor of puromycin-sensitive aminopeptidase with a homophthalimide skeleton: Identification of the target molecule and a structure-activity relationship study Reviewed

    M Komoda, H Kakuta, H Takahashi, Y Fujimoto, S Kadoya, F Kato, Y Hashimoto

    BIOORGANIC & MEDICINAL CHEMISTRY   9 ( 1 )   121 - 131   2001.1

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    DOI： 10.1016/S0968-0896(00)00231-5

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  • Novel Specific Puromycin-sensitive Aminopeptidase Inhibitors: 3-(2,6-Diethylphenyl)-2,4(1H,3H)quinazolinedione and N-(2,6-Diethylphenyl)-2-amino-4H-3,1-benzoxazin-4-one Reviewed

    Hiroki Kakuta, Yukiko Koiso, Hiroyasu Takahashi, Kazuo Nagasawa, and Yuichi Hashimoto

    HETEROCYCLES   55 ( 8 )   1433 - 1438   2001

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    DOI： 10.3987/com-01-9247

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  • Aromatic layered guanidines bind sequence-specifically to DNA minor groove with precise fit Reviewed

    Ryuuta Fukutomi, Aya Tanatani, Hiroki Kakuta, Nobuo Tomioka, Akiko Itai, Yuichi Hashimoto, Koichi Shudo, Hiroyuki Kagechika

    Tetrahedron Letters   39 ( 36 )   6475 - 6478   1998.9

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    DOI： 10.1016/s0040-4039(98)01378-1

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▼display all

Books

  • MEDCHEM NEWS

    HIROKI KAKUTA（Anti-inflammatory Bowel Disease Drug Discovery Targeting Retinoid X Receptors）

    2022.11 

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  • 現代化学

    東京化学同人  2007 

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  • ファルマシア6月号

    社団法人日本薬学会  2004 

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MISC

  • F-containing retinoid X receptor (RXR) partial agonist F-CBt-PMN whose tissue transferability is affected by coadministration of another RXR ligand

    Yuta Takamura, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Masaru Akehi, Takanori Sasaki, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   258   2019.8

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  • 経口吸収性RXRアンタゴニストの創出とその2型糖尿病モデルでの薬効評価

    渡邉 将貴, 藤原 美智子, 西井 緑, 加来田 博貴

    ビタミン   92 ( 4 )   230 - 230   2018.4

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  • PETイメージングに期待するビタミン研究の新展開

    加来田 博貴

    ビタミン   92 ( 4 )   194 - 195   2018.4

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  • 催奇形性軽減化を志向した新規レキシノイドの創出研究

    高村 祐太, 芝原 理, 渡邉 将貴, 高橋 愛海, 西井 緑, 藤原 美智子, 加来田 博貴

    ビタミン   92 ( 4 )   230 - 230   2018.4

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  • 経口吸収性を担保した新規RXRアンタゴニストの創出

    渡邉 将貴, 藤原 美智子, 加来田 博貴

    日本薬学会年会要旨集   138年会 ( 2 )   114 - 114   2018.3

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  • 研究公正化、医薬品開発のスピードアップのための「信頼性確保の知識・方法論」の産学官での共有を目指して アカデミアでの悩み、それを解決するには?

    加来田 博貴

    日本薬学会年会要旨集   138年会 ( 1 )   143 - 143   2018.3

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  • hRXRαリガンドCBt-PMNのパーシャルアゴニスト活性の起源は何か?

    清水 奏, 宮下 由里奈, 松尾 直也, 中野 祥吾, 伊藤 創平, 沼本 修孝, 伊倉 貞吉, 伊藤 暢聡, 加来田 博貴, 常盤 広明

    日本薬学会年会要旨集   138年会 ( 2 )   111 - 111   2018.3

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  • X線結晶構造及び相互作用解析に基づく蛍光性RXRαアゴニスト作用機序の解明

    川崎真由, 中野祥吾, 本山智晴, 山田翔也, 渡邉将貴, 藤原美智子, 常盤広明, 加来田博貴, 伊藤創平

    メディシナルケミストリーシンポジウム講演要旨集   36th   2018

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  • 核内受容体転写因子複合体におけるRXRαパーシャルアゴニストのPPI制御能に関する構造生物学,熱化学,および理論化学的解析

    清水奏, 宮下由里奈, 中野祥吾, 伊藤創平, 沼本修孝, 伊倉貞吉, 伊藤暢聡, 加来田博貴, 常盤広明

    創薬懇話会講演要旨集   2018   2018

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  • Synthesis of 11C labeled RXR partial agonist CBt-PMN by [11C] carbon dioxide fixation via organolithiation of trialkyltin precursor and PET imaging thereof

    Osamu Shibahara, Masaki Watanabe, Masaru Akehi, Takanori Sasaki, Takahisa Hanada, Akiya Akahoshi, Hiroyuki Hirano, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   254   2017.8

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  • PETイメージングを用いたRXRパーシャルアゴニストCBt-PMNの脳移行性の評価

    芝原 理, 小林 俊貴, 渡邊 将貴, 西井 緑, 明日 卓, 佐々木 崇了, 赤星 彰也, 花田 貴寿, 平野 裕之, 加来田 博貴

    日本薬学会年会要旨集   137年会 ( 2 )   118 - 118   2017.3

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  • レチノイドX受容体パーシャルアゴニストCBt-PMNの認知症改善効果

    加来田 博貴, 小林 俊貴, 山田 翔也, 芝原 理, 藤原 美智子, 西井 緑

    ビタミン   90 ( 4 )   176 - 176   2016.4

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  • レチノイド関連化合物による肝癌細胞特異的な増殖抑制効果と機能解析

    坪田 智明, 神吉 けい太, 影近 弘之, 高橋 典子, 加来田 博貴, 汐田 剛史

    肝臓   57 ( Suppl.1 )   A253 - A253   2016.4

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  • RXRパーシャルアゴニストに関する理論的研究

    夏目 継介, 松尾 直也, 岡崎 誠司, 中野 祥吾, 伊藤 創平, 加来田 博貴, 常盤 広明

    日本薬学会年会要旨集   136年会 ( 2 )   170 - 170   2016.3

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  • レチノイドX受容体を標的とした創薬に関する研究

    加来田 博貴

    ビタミン   90 ( 3 )   101 - 108   2016.3

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    DOI： 10.20632/vso.90.3_101

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    Other Link： http://search.jamas.or.jp/link/ui/2016224078

  • アレルギー性気道炎症マウスモデルにおけるレチノイドX受容体(RXR)パーシャルアゴニストの治療効果に関する研究

    藤井 詩子, 金廣 有彦, 谷口 暁彦, 森近 大介, 小田 尚廣, 栗本 悦子, 古賀 光, 早稲田 公一, 加来田 博貴, 宮原 信明, 木浦 勝行, 谷本 光音

    日本呼吸器学会誌   5 ( 増刊 )   178 - 178   2016.3

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  • iPSC-derived cancer stem cells provide a model of tumor vasculature Reviewed International journal

    Hiroki Kakuta

    American journal of cancer research   6 ( 9 )   1906 - 1921   2016

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  • 生細胞内のアスコルビン酸濃度分布のイメージング化に関する試み

    田井 章博, 石股 直, 加来田 博貴

    ビタミン   89 ( 12 )   595 - 596   2015.12

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    DOI： 10.20632/vso.89.12_595_2

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  • 関節軟骨造影剤を用いた関節軟骨プロテオグリカンの評価

    大橋 俊孝, 加来田 博貴, 芳谷 学, 山田 翔也, 大月 孝志, 廣畑 聡, 二宮 善文, 西田 圭一郎

    日本結合組織学会学術大会プログラム・抄録集   47回   97 - 97   2015.5

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  • レチノイドX受容体を標的とした創薬に関する研究

    加来田 博貴

    ビタミン   89 ( 4 )   177 - 178   2015.4

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    DOI： 10.20632/vso.89.4_177

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  • 新規RXRパーシャルアゴニストCBt-PMNの炎症性腸疾患モデルにおける有効性の検討

    滝澤 慧, 古澤 之裕, 古沢 優貴, 小林 俊貴, 山田 翔也, 加来田 博貴, 長谷 耕二

    日本薬学会年会要旨集   135年会 ( 3 )   97 - 97   2015.3

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  • RXR partial agonist NEt-4IB exerts therapeutic effects on inflammatory bowel disease without the side effects of RXR full agonists

    Yuki Furusawa, Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Shoya Yamada, Makoto Makishima, Akihiro Tai, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014.8

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  • Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging

    Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Yuki Furusawa, Shoya Yamada, Hiroyuki Hirano, Fumiaki Takenaka, Masaru Akehi, Takanori Sasaki, Eiji Matsuura, Akihiro Tai, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014.8

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  • Development of fluorescent retinoid X receptor ligands and Forster resonance energy transfer (FRET)-based RXR ligand screening method

    Shoya Yamada, Mariko Nakayama, Kazutaka Kohara, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014.8

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  • 新規X線造影剤による変形性膝関節症ラット関節軟骨の高解像度マイクロCT造影

    大橋 俊孝, 加来田 博貴, 芳谷 学, 大月 孝志, 大野 充昭, 山田 翔也, 前原 亜美, 廣畑 聡, 西田 圭一郎, 窪木 拓男, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   46回・61回   106 - 106   2014.6

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  • PETイメージングを用いたアルコキシ基を有するレチノイドX受容体アゴニストの体内動態解析

    加来田 博貴, 小林 俊貴, 古沢 優貴, 山田 翔也, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博

    ビタミン   88 ( 4 )   213 - 213   2014.4

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  • アルコキシ基を有するレチノイドX受容体アゴニストの位置異性体間における体内動態差の解明とその応用

    小林 俊貴, 古沢 優貴, 山田 翔也, 平野 裕之, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博, 加来田 博貴

    日本薬学会年会要旨集   134年会 ( 4 )   81 - 81   2014.3

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  • 高精度第一原理計算およびMDシミュレーションを用いた核内受容体AF2インターフェースの動的構造解析

    丸藤 友彦, 石坪 江梨花, 加来田 博貴, 山田 幸子, 槇島 誠, 常盤 広明

    日本薬学会年会要旨集   134年会 ( 2 )   81 - 81   2014.3

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  • Retinoid X receptor ligands: a patent review (2007 - 2013) Reviewed

    Hiroki Kakuta

    Expert opinion on therapeutic patents   24 ( 4 )   443 - 452   2014

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  • リジンオリゴマーからなる関節軟骨特異的X線プローブの創出

    大橋俊孝, 芳谷学, 大野充昭, 山田翔也, 大月孝志, 前原亜美, 廣畑聡, 西田圭一郎, 窪木拓男, 加来田博貴, 二宮善文

    日本軟骨代謝学会プログラム・抄録集   27th   2014

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  • Structurally simple cartilage probes constructed with epsilon-lysine oligomers targeting chondroitin sulfates

    Hiroki Kakuta, Manabu Hagaya, Shoya Yamada, Fuminori Ohsawa, Ami Maehara, Aki Yoshida, Mitsuaki Ono, Ryuichi Nakahara, Keiichiro Nishida, Toshitaka Oohashi

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   246   2013.9

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  • Development of fluorescent retinoid X receptor ligands as a ligand screening tool

    Shoya Yamada, Mariko Nakayama, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   246   2013.9

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  • レチノイドX受容体パーシャルアゴニストNEt-4IBの創出と薬効・副作用評価

    加来田 博貴, 川田 浩平, 中山 真理子, 山田 翔也, 小林 俊貴, 古沢 優貴, 大橋 俊孝, 田井 章博, 矢間 太

    ビタミン   87 ( 4 )   254 - 254   2013.4

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  • レチノイドX受容体を標的とするリガンド探索ツールとしての蛍光性リガンドの開発研究

    山田 翔也, 小原 一剛, 中山 真理子, 槙島 誠, 内藤 博敬, 加来田 博貴

    日本薬学会年会要旨集   133年会 ( 2 )   70 - 70   2013.3

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  • Discovery and application of a fluorescent RXR antagonist to fluorescence polarization assay

    Shoya Yamada, Mariko Nakayama, Fuminori Ohsawa, Makoto Makishima, Hirotaka Naitou, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   244   2012.8

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  • Discovery of a novel benzotriazole-type retinoid X receptor partial-agonist decreasing plasma glucose level in type-2 diabetes mellitus with decreased side effects

    Hiroki Kakuta, Nobumasa Yakushiji, Fuminori Ohsawa, Shoya Yamada, Mariko Nakayama, Kohei Kawata, Yui Ohta, Chisa Fujiwara, Toshitaka Oohashi, Makoto Makishima, Akihiro Tai, Hiroyuki Yasui, Yutaka Yoshikawa

    CANCER RESEARCH   72   2012.4

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    DOI： 10.1158/1538-7445.AM2012-946

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  • 新規RXRアゴニスト及びその類縁化合物のヒト肝における代謝特性の予測

    合葉 哲也, 村上 由樹, 清水 康正, 川田 浩平, 中山 真理子, 小笠原 明美, 岡田 淳芳, 黒崎 勇二, 加来田 博貴

    日本薬学会年会要旨集   132年会 ( 2 )   269 - 269   2012.3

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  • 関節軟骨に特異的に結合するX線造影化イメージングプローブの創出研究

    芳谷 学, 大澤 史宜, 加来田 博貴, 大橋 俊孝

    日本薬学会年会要旨集   132年会 ( 2 )   271 - 271   2012.3

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  • チアゾリジンジオン誘導体GPU-4の網膜血管新生抑制作用

    中村 信介, 林 慧, 瀧澤 悠加, 村瀬 哲司, 鶴間 一寛, 嶋澤 雅光, 加来田 博貴, 永澤 秀子, 原 英彰

    日本薬理学雑誌   139 ( 3 )   27P - 27P   2012.3

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  • RXRアゴニストCBt-PMNのパーシャルアゴニスト活性発現機構の解明

    大澤 史宜, 薬師寺 信匡, 篠崎 亮介, 山田 翔也, 中山 真理子, 川田 浩平, 槇島 誠, 加来田 博貴

    日本薬学会年会要旨集   132年会 ( 2 )   165 - 165   2012.3

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  • 蛍光性RXRリガンドの創出とRXRリガンド探索への応用

    山田 翔也, 中山 真理子, 大田 由衣, 槇島 誠, 内藤 博敬, 加来田 博貴

    日本薬学会年会要旨集   132年会 ( 2 )   166 - 166   2012.3

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  • RXRパーシャルアゴニストの創出ならびに乾癬モデルマウスでの有効性・副作用発現の評価

    川田 浩平, 中山 真理子, 森下 健一, 大澤 史宜, 山田 翔也, 大田 由衣, 加来田 博貴

    日本薬学会年会要旨集   132年会 ( 2 )   269 - 269   2012.3

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  • メントン由来の二環性骨格を有する9-cis-レチノイン酸誘導体型RXRアゴニストの創製

    沖津貴志, 山田翔也, 加来田博貴, 和田昭盛

    メディシナルケミストリーシンポジウム講演要旨集   30th   2012

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  • 糖尿病治療に挑む新しい薬剤開発 「教育・臨床現場の声」と「天然物・有機・無機化合物」からのアプローチ レチノイドX受容体を標的に単剤1型・2型糖尿病治療薬候補化合物創製に挑む

    加来田 博貴

    薬学雑誌   131 ( 6 )   917 - 923   2011.6

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    DOI： 10.1248/yakushi.131.917

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  • 有機合成化学の若い力 創造への挑戦 リバイバル創薬

    加来田 博貴

    日本薬学会年会要旨集   131年会 ( 1 )   160 - 160   2011.3

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  • Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors

    Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Hiroki Kakuta

    Yakugaku Zasshi   131 ( 3 )   347 - 351   2011.3

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    DOI： 10.1248/yakushi.131.347

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  • 炎症性サイトカインを用いた腸疾患のイメージングと治療薬薬効評価法の検討

    赤田 直輝, 東川 桂, 八木 克治, 渡辺 恵子, 加来田 博貴, 廣村 信, 榎本 秀一

    日本薬学会年会要旨集   131年会 ( 3 )   188 - 188   2011.3

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  • [Challenge of creating single-agents for the treatment of type 1 and 2 diabetes by targeting retinoid X receptor] Reviewed

    Hiroki Kakuta

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   131 ( 6 )   917 - 923   2011

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  • [Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors] Reviewed

    Hiroki Kakuta

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   131 ( 3 )   347 - 351   2011

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  • Tchreg細胞株(HOZOT)における核内受容体RXRαとPPARγの発現、細胞内局在並びに機能解析(Expression kinetics, subcellular localization, and functional properties of RXRα and PPARγ in Tchreg (cytotoxic, helper, and regulatory T) cell line, HOZOT)

    鈴木 基之, 山崎 史行, 加来田 博貴

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   1P - 0364   2010.12

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  • シクロオキシゲナーゼ1(COX‐1)阻害を基盤としたベンズアニリド骨格を有する新規鎮痛剤の創製

    深井良祐, ZHENG Xiaoxio, 本島和典, 田井章博, 矢間太, 加来田博貴

    メディシナルケミストリーシンポジウム講演要旨集   29th   144 - 145   2010.10

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  • 医薬化学 インスリンに頼らず血糖値を下げる肝臓選択的グルコキナーゼ活性化剤

    加来田 博貴

    ファルマシア   46 ( 6 )   559 - 560   2010.6

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  • 新規骨格を有するRXRアゴニストの体内動態に関する基礎的検討

    村上 由樹, 小笠原 明美, 大澤 史宜, 合葉 哲也, 川崎 博己, 加来田 博貴, 黒崎 勇二

    日本薬学会年会要旨集   130年会 ( 4 )   265 - 265   2010.3

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  • Pioglitazoneの抗炎症作用における作用機序に関する研究

    山本 篤毅, 杉山 茉由, 妹尾 訓枝, 日下 絵梨子, 篠崎 亮介, 加来田 博貴, 杉本 幸雄

    日本薬理学雑誌   135 ( 3 )   21P - 21P   2010.3

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  • 糖尿病治療に挑む新しい薬剤開発 「教育・臨床現場の声」と「天然物・有機・無機化合物」からのアプローチ レチノイドX受容体を標的に単剤1型2型糖尿病治療薬候補化合物創製に挑む

    加来田 博貴

    日本薬学会年会要旨集   130年会 ( 1 )   221 - 221   2010.3

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  • 次世代の創薬研究を担う若手研究者のチカラ 大学におけるメディシナルケミストリー シクロオキシゲナーゼ-1(COX-1)阻害剤の開発意義とその創出

    深井 良祐, 鄭 暁霞, 本島 和典, 加来田 博貴

    日本薬学会年会要旨集   130年会 ( 1 )   394 - 394   2010.3

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  • 核内受容体RXRアゴニストのマウス鼻アレルギーモデルに対する効果について

    杉山 茉由, 山本 篤毅, 篠崎 亮介, 日下 絵梨子, 妹尾 訓枝, 宮地 弘幸, 加来田 博貴, 杉本 幸雄

    日本薬理学雑誌   135 ( 3 )   21P - 21P   2010.3

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  • NOの被観血的、非侵襲的な定量法の開発とアレルギーモデルでの検証

    高島 征助, 妹尾 訓枝, 山本 篤毅, 杉本 幸雄, 加来田 博貴

    日本薬学会年会要旨集   130年会 ( 3 )   138 - 138   2010.3

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  • 新規低脂溶性RARβ選択的アゴニストの創製研究

    大澤 史宜, 山田 翔也, 山本 篤毅, 深井 良祐, 鄭 霞暁, 槇島 誠, 杉本 幸雄, 田井 章博, 加来田 博貴

    日本薬学会年会要旨集   130年会 ( 2 )   243 - 243   2010.3

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  • 脂溶性低減を志向したカルボン酸等価体を有する新規RXRアゴニストの創製研究

    藤井 周司, 大澤 史宜, 深井 良祐, 山田 翔也, 槇島 誠, 加来田 博貴

    日本薬学会年会要旨集   130年会 ( 2 )   243 - 243   2010.3

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  • 炎症性サイトカインを標的とする潰瘍性大腸炎診断プローブの探索

    東川 桂, 八木 克治, 渡辺 恵子, 加来田 博貴, 金山 洋介, 廣村 信, 榎本 秀一

    日本薬学会年会要旨集   130年会 ( 4 )   125 - 125   2010.3

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  • カラゲニン浮腫試験に対するRXRアゴニストNEt-3IPの効果

    山本 篤毅, 杉山 茉由, 篠崎 亮介, 宮地 弘幸, 加来田 博貴, 杉本 幸雄

    日本薬理学雑誌   134 ( 4 )   11P - 11P   2009.10

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  • 核内受容体RXRアゴニストの抗アレルギー作用について

    杉山 茉由, 山本 篤毅, 篠崎 亮介, 宮地 弘幸, 加来田 博貴, 杉本 幸雄

    日本薬理学雑誌   134 ( 4 )   10P - 10P   2009.10

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  • Design and in vitro/in vivo evaluation of novel Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy4-isopropylphenylamino Moiety, NEt-3IP.

    Hiroki Kakuta, Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Ken-ichi Morishita, Makoto Makishima, Shigeyuki Uno, Yukio Sugimoto

    CANCER RESEARCH   69   2009.5

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  • 新規レチノイドX受容体アゴニストNEt-3IPのラットにおける体内動態評価

    小笠原 明美, 薬師寺 信匡, 合葉 哲也, 川崎 博己, 黒崎 勇二, 加来田 博貴

    日本薬学会年会要旨集   129年会 ( 4 )   220 - 220   2009.3

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  • RXRアゴニストNEt-3IPの抗アレルギー作用について

    加来田 博貴, 久山 翔司, 尾崎 友美, 杉山 茉由, 宇野 茂之, 槇島 誠, 森下 健一, 鄭 暁霞, 原田 隼, 杉本 幸雄

    日本薬学会年会要旨集   129年会 ( 2 )   114 - 114   2009.3

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  • チアゾリジンジオン骨格を有する新規選択的血管新生阻害剤GPU-4の開発

    林 慧, 三原 法秀, 岡部 泰之, 上田 聡, 奥田 健介, 加来田 博貴, 松永 望, 原 英彰, 永澤 秀子

    日本薬学会年会要旨集   129年会 ( 2 )   114 - 114   2009.3

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  • RXRアゴニストNEt-3IPの樹状細胞分化抑制・制御性T細胞誘導能と抗アレルギー作用

    加来田博貴, 大澤史宜, 杉山茉由, 杉本幸雄, 槇島誠, 鈴木基之, 中村修治

    メディシナルケミストリーシンポジウム講演要旨集   28th   2009

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  • カラゲニン浮腫試験に対するRXRアゴニストNEt-3IPの効果

    山本篤毅, 杉山茉由, 篠崎亮介, 宮地弘幸, 加来田博貴, 杉本幸雄

    日本薬理学会近畿部会プログラム・要旨集   115th   2009

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  • 抗がん・抗炎症・抗アレルギー剤を指向した低脂溶性レキシノイド (特集 バイオ応用技術の最前線)

    加来田 博貴

    ケミカルエンジニヤリング   53 ( 11 )   855 - 860   2008.11

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  • シクロオキシゲナーゼ1阻害剤は胃潰瘍形成のない魅力的な抗がん剤候補である。ベンズアミドタイプのCOX-1阻害剤による提示。(COX-1-selective inhibitors are attractive candidates for anti-cancer agents that do not cause gastric damage)

    加来田 博貴, 鄭 曉霞, 小田 博之, 原田 隼, 杉本 幸雄, 永澤 秀子, 佐々木 健二, 田井 章博

    日本癌学会総会記事   67回   369 - 369   2008.9

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  • 強い新規血管新生阻害作用を有するチアゾリジンジオン誘導体の分子設計、合成及び生物活性評価(Design, synthesis, and biological evaluation of potent anti-angiogenic thiazolidinedione derivatives)

    永澤 秀子, 林 慧, 岡部 泰之, 上田 聡, 加来田 博貴

    日本癌学会総会記事   67回   306 - 306   2008.9

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  • 環状イミド構造を有する新規血管新生阻害剤の分子設計

    林 慧, 岡部 泰之, 須藤 智美, 三原 法秀, 上田 聡, 加来田 博貴, 永澤 秀子

    日本薬学会年会要旨集   128年会 ( 2 )   52 - 52   2008.3

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  • 新規シクロオキシゲナーゼ1(COX-1)阻害剤の開発とその胃潰瘍形成の有無および鎮痛効果の検証

    加来田 博貴, 鄭 暁霞, 小田 博之, 原田 隼, 大澤 史宜, 藤井 周司, 永澤 秀子, アリ・ハメッド, 赤穂 榮一, 佐々木 健二, 杉本 幸雄, 田井 章博

    日本薬学会年会要旨集   128年会 ( 2 )   51 - 51   2008.3

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  • RXRα/βデュアルアゴニストNEt-3IPの開発と生理活性評価

    高松 佳代, 高野 敦史, 薬師寺 信匡, 師橋 一徳, 森下 健一, 大澤 史宜, 藤井 周司, 松浦 信康, 槇島 誠, 永澤 秀子, 杉本 幸雄, 田井 章博, 佐々木 健二, 加来田 博貴

    日本薬学会年会要旨集   128年会 ( 2 )   51 - 51   2008.3

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    J-GLOBAL

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  • RXRα/βデュアルアゴニストNEt-3IPの抗炎症及び抗がん作用の検証

    高野敦史, 原田隼, ZHENG Xiaoxia, 薬師寺信匡, 森下健一, 大澤史宜, 藤井周司, 杉本幸雄, 田井章博, 槇島誠, 永澤秀子, 佐々木健二, 加来田博貴

    メディシナルケミストリーシンポジウム講演要旨集   26th   2007

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  • ベンゼンスルホンアニリドを骨格とする新規シクロオキシゲナーゼ阻害剤の開発

    鄭 暁霞, 小田 博之, 片山 健太郎, 赤穂 栄一, Hamed I. Ali, 加来田 博貴, 佐々木 健二

    日本薬学会年会要旨集   126年会 ( 4 )   175 - 175   2006.3

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  • ピューロマイシン感受性アミノペプチダーゼ(PSA)特異的阻害剤の構造活性相関

    加来田 博貴, 柏 延之, 小磯 邦子, 長澤 和夫, 橋本 祐一

    日本薬学会年会要旨集   122年会 ( 3 )   10 - 10   2002.3

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  • ホモフタルイミド型特異的アミノペプチダーゼ阻害剤の構造活性相関

    加来田 博貴, 門矢 静夫, 高橋 裕保, 森崎 尚子, 佐崎 敬三, 橋本 祐一

    日本薬学会年会要旨集   121年会 ( 3 )   21 - 21   2001.3

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  • Enzyme Inhibitors Derived from Thalidomide

    Hiroki Kakuta, Hiroyasu Takahashi, Sonei Sou, Tetsuya Kita, Kazuo Nagasawa, Yuichi Hashimoto

    Recent Res. Devel. Med. Chem.   1, 189-211   2001

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  • Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton

    H Takahashi, M Komoda, H Kakuta, Y Hashimoto

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   120 ( 10 )   909 - 921   2000.10

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    Language：Japanese   Publishing type：Book review, literature introduction, etc.  

    DOI： 10.1248/yakushi1947.120.10_909

    Web of Science

    CiNii Article

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  • Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton

    H Takahashi, M Komoda, H Kakuta, Y Hashimoto

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   120 ( 10 )   909 - 921   2000.10

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    Language：Japanese   Publishing type：Book review, literature introduction, etc.  

    DOI： 10.1248/yakushi1947.120.10_909

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Presentations

  • A Green and Scale-up Synthesis of Retinoid X Receptor Agonist NEt-3IB Invited

    Takamura, Yuta, Morishita, Ken-ichi, Kikuzawa, Shota, Watanabe, Masaki, Kakuta, Hiroki

    PacifiChem2021 

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    Event date： 2021.12.16 - 2021.12.21

    Language：English   Presentation type：Oral presentation (invited, special)  

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  • GatekeeperレチノイドX受容体アンタゴニストCBTF-EEを骨格とする新規蛍光性RXRアンタゴニストの創出とリガンド結合試験法への展開

    高村祐太, 瀧奥真歩, 藤原美智子, 川﨑真由, 中野祥吾, 加来田博貴

    日本ビタミン学会第73回大会  2021.6.12 

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    Presentation type：Oral presentation (general)  

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  • ヒドロキサム酸を有さない新規 MMP 阻害剤の開発研究 発表形式：ポスター

    日本薬学会第１２９年会  2010 

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  • チアゾリジンジオン骨格を有する新規選択的血管新生阻害剤GPU-4の開発 発表形式：ポスター

    日本薬学会第１２９年会  2010 

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  • RXRアゴニスト NEt-3IPの抗アレルギー作用について

    日本薬学会第１２９年会  2010 

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  • 新規レチノイドX受容体アゴニスト NEt-3IP のラットにおける体内動態評価

    日本薬学会第１２９年会  2010 

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  • RXRアゴニストNEt-3IPの樹状細胞分化抑制・制御性T細胞誘導能と抗アレルギー作用

    メディシナルケミストリーシンポジウム  2009 

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  • パーミッシブ機構に着目したRXRパーシャルアゴニストの挙動検証

    創薬懇話会2009  2009 

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  • 白血病治療薬を志向した新規低脂溶性RARβ選択的アゴニストの創製研究

    メディシナルケミストリーシンポジウム  2009 

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  • COX-1-selective inhibitors are new attractive agents for cancer treatment without the gastric damage: Design, in vitro and in vivo evaluation of a structurally-simple benzamide-type COX-1 selective inhibitor, TFAP

    American Association for Cancer Research Annual Meeting 2008  2008 

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  • RXRα/β選択的アゴニストNEt-3IPの開発と生理活性

    レチノイド研究会  2007 

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  • COX-1-selective inhibitors are new attractive targets for analgesics without the gastric damage. Design, in vitro and in vivo evaluation of structurally-simple COX-1 inhibitors

    Takeda Symposium  2007 

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  • 安価なイソニコチン酸から2ステップで合成可能な ビスカチオン型抗マラリア化合物の開発

    メディシナルケミストリーシンポジウム（相模原）  2007 

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  • RXRα/βデュアルアゴニストNEt-3IPの抗炎症及び抗がん作用の検証

    メディシナルケミストリーシンポジウム  2007 

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  • 高活性RXRα/β選択的アゴニストNEt-3IPの開発 －脂溶性部位にアルコキシ基を有する－

    メディシナルケミストリーシンポジウム  2007 

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  • RXRアゴニスト脂溶性部位の脂溶性低減によるRXRサブタイプ指向性の創出 ―リンカー部位にスルホンアミド基を有する―

    メディシナルケミストリーシンポジウム  2007 

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  • 一工程で合成可能な非サルファ剤型抗MRSA・VREベンゼンスルホンアニリド誘導体

    メディシナルケミストリーシンポジウム  2007 

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  • 安価なイソニコチン酸から2ステップで合成可能なビスカチオン型抗マラリア化合物の開発

    メディシナルケミストリーシンポジウム  2007 

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  • 胃腸障害のない鎮痛化合物創出を志向したシクロオキシゲナーゼ１（COX-1）阻害剤の開発

    日本薬学会中国四国支部学術大会  2007 

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  • アミド部位を N-アルキル化したピリジニウム塩ダイマーの抗マラリア活性の検討

    メディシナルケミストリーシンポジウム  2006 

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  • 胃潰瘍形成の無い鎮痛剤開発を目指した新規シクロオキシゲナーゼ１(COX-1)選択的阻害剤の創製

    メディシナルケミストリーシンポジウム  2006 

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  • 6-Phenylaminonicotinic acidを共通骨格とする複素環RXRリガンドの開発

    複素環化学討論会  2006 

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  • リンカーとしてN, N’-アルキル鎖を有するピリジニウム塩ダイマーの抗マラリア活性

    複素環化学討論会  2006 

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  • Antimalarial effect of bis-ptridinium salts

    環太平洋国際化学会議(2005)  2005 

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  • スルホンアミド構造を有する新規RXRリガンドの創製

    メディシナルケミストリーシンポジウム  2005 

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  • 2,4(1H,4H)Quinazolinedioneを骨格とするレチノイドアンタゴニストの創製

    第４４回日本薬学会・日本薬剤会中国四国支部学術大会  2005 

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  • バイオイメージングを志向した蛍光性レチノイドの開発

    第４４回日本薬学会・日本薬剤会中国四国支部学術大会  2005 

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  • Benzanilideを骨格とする新規cyclooxygenase-1(COX-1)選択的阻害剤の創製

    第４４回日本薬学会・日本薬剤会中国四国支部学術大会  2005 

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  • Ｎ－アルキル鎖を有するピリジニウム塩ダイマーの抗マラリア活性

    第３５回複素環化学討論会  2005 

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  • Design and Synthesis of Novel Cyclooxygenase Inhibitors with a Benzenesulfonamide Skeleton

    環太平洋国際化学会議（2005)  2005 

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  • 細胞分化を制御する複素環化合物の創製

    第34回複素環化学討論会  2004 

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  • ベンゼンスルフォンアニリドの立体特性を利用した新規COX-2特異的阻害剤の開発研究

    第43回日本薬学会・日本病院薬剤師会 中国四国支部学術大会  2004 

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  • ピューロマイシン感受性アミノペプチダーゼを標的とした鎮痛剤の開発研究

    日本薬学会 第124年会  2004 

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  • サリドマイドの構造展開による選択的COX阻害剤の創製および構造活性相関

    日本薬学会 第123年会  2003 

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  • 抗マラリア活性を有するアンモニウム塩ダイマーの合成

    第33回複素環化学討論会  2003 

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  • Syntheses of Thiopyrone and Pyrone Derivatives by Photocyclization Reaction of 3-Aryl-2-([1]benzothien-3-yl)propenoic Acids

    国際へテロ環学会  2003 

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  • ピューロマイシン感受性アミノペプチダーゼ(PSA)特異的阻害剤の構造活性相関

    日本薬学会 第122年会  2002 

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  • ホモフタルイミド型特異的アミノペプチダーゼ阻害剤の構造活性相関

    日本薬学会 第121年会  2001 

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  • Novel Specific Inhibitors of Puromycin-Sensitive Aminopeptidase

    国際ヘテロ環学会  2001 

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  • 芳香族環状N-メチル化アミドの立体挙動

    日本薬学会 第120年会  2000 

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Industrial property rights

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Awards

  • The Uchiyama Yuzo Science and Technology Award

    2020.7   Okayama Foundation for Science and Technology  

    Hiroki Kakuta

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  • Science and Technology Award in Okayama Foundation of Science and Technology

    2015.7   Okayama Foundation for Science and Technology  

    KAKUTA Hiroki

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  • 日本ビタミン学会賞（奨励賞）

    2015.6   日本ビタミン学会   レチノイドＸ受容体を標的とした創薬に関する研究

    加来田 博貴

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  • 2011 Young Top Researcher Award

    2012.2   Okayama University  

    KAKUTA Hiroki

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  • Award for Excellent General Presentation in the Medicinal Chemistry Symposium

    2010.11  

    KAKUTA Hiroki

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  • 日本薬学会中国四国支部奨励賞

    2008.11  

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    Country：Japan

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Research Projects

  • Creation of new agents for BNCT that enable to measure boron concentration at tumor site

    Grant number：19K05735  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kakuta Hiroki

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    Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）

    Boron neutron capture therapy (BNCT) depends on the collision of 10B and neutrons, so the concentration of boron in the cancer tissue is an important factor. However, there is no boron compounds whose boron concentration in cancer tissue can be measured. In this study, we aimed to create new compounds for BNCT to solve this problem. Focusing on the quantification of iodine concentration in X-ray CT, we designed compounds having diiodobenzene and BSH, which is a boron cluster. Among them, BS-DIP-OEF (3c), which has a fluoroethyl group, showed quantifiability in X-ray CT at iodine concentrations above 800 ppm. When neutron beam irradiation is performed on the cells treated with 3c, the boron neutron capture reaction (BNCR) were highly correlated with intracellular boron concentration.

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  • Establishment of in vivo imaging and quantification of articular cartilage by using a cartilage-specific probe.

    Grant number：15K15551  2015.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Oohashi Toshitaka, HIROHATA Satoshi, OHTSUKI Takakashi, ASZDI Attila

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    Grant amount：\3640000 （ Direct expense: \2800000 、 Indirect expense：\840000 ）

    A new X-ray imaging probe 2Ke2-TIB has been created in addition to Ke4-TIB. These probes were examined for in vivo imaging of articular cartilage by CT using rat osteoarthritic model. A new patent regarding Ke4-TIB has been established on March 24th, 2017. Since we speculate the increasing use of mouse genetic model for drug discovery research, we created a new mouse genetic model by crossing floxed "A" gene mice, encoding a proteoglycan gene abundant in the articular cartilage, with Rosa26-creERT mice. The mice exhibited a dwarfism and articular cartilage degeneration after starting injection of tamoxifen at one week of age. These developments of new imaging probes and a mouse model will contribute to the future research on osteoarthritis drug discovery. A collaboration with a group in the University of Munich has started for nano Xray CT.

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  • Development of the strategy for fundamental therapy of cancer using iPS derived Cancer Stem cell models

    Grant number：25242045  2013.10 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)  Grant-in-Aid for Scientific Research (A)

    Seno Masaharu

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    Grant amount：\32890000 （ Direct expense: \25300000 、 Indirect expense：\7590000 ）

    For the purpose of the development of the fundamental therapeutic strategies to target cancer stem cells (CSCs), we have been taking advantage of iPS-derived CSCs (iPS-CSCs). In this project, we have proven the direct contribution of CSCs to tumor vasculature development, and have established a new model of pancreatic CSCs. In addition, we performed gene expression profiling of CSCs. These results should be valuable to identify new therapeutic target molecule(s) in CSCs and cancer niche. We also performed drug screening, tried to design new drug. Among the several approved anticancer drugs, we found a drug showing highly effective to iPS-CSCs.

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  • Exploratory research of high activity metal complexes by organic and inorganic nano-composite with anti-diabetic effect

    Grant number：25460048  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YOSHIKAWA Yutaka, KAKUTA Hiroki, NAITO Yuki

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    Grant amount：\5200000 （ Direct expense: \4000000 、 Indirect expense：\1200000 ）

    In this study, we synthesized various metal complexes with organic compounds, medicine, and natural products. Above the results, we suggested that the metal complex with the high anti-diabetic effect was Zn complex with ZnS2O2 or ZnSe2O2 coordination mode. These complexes showed the blood glucose normalizing, anti-insulin resistance, and glucose tolerance improved effects by using type 2 diabetes mellitus model KKAy or obob mice. Moreover, Zn complexes activates the insulin signaling pathway with inducing Akt phosphorylation by a insulin-independent manner. It is suggested that this signal activation of Zn complexes in insulin signaling pathway has the potent to ameliorate the insulin resistance in the peripheral tissues; such as muscles and adipose. And it is expectable that this would be the novel mechanism for the treatment of DM.

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  • Creation of articular cartilage-specific bio-molecular imaging probe with potentials of dual modalities.

    Grant number：25670648  2013.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    OOHASHI Toshitaka, NISHIDA Keiichiro, KAKUTA Hiroki

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    Grant amount：\3770000 （ Direct expense: \2900000 、 Indirect expense：\870000 ）

    In the process of cartilage degeneration seen in osteoarthritis, loss of proteoglycan from articular cartilage has been widely accepted as a critical early event. We investigated bio-molecular imaging of articular cartilage using our molecular probes targeting articular GAGs.
    Chondroitin sulfate, a major component of articular cartilage, has negative charge caused by sulfates. We designed lysine oligomers (monomer - pentamer) which were connected with the a-carboxyl and e-amino group. These lysine oligomers possess e-amino groups as cationic moieties. Then, we created a novel articular cartilage imaging X-ray probe Ke4-triiodobenzene (Ke4-TIB) and demonstrated an ex vivo imaging of articular cartilage in rat osteoarthritic models. The imaging could quantitate loss of proteoglycan from osteoarthritic cartilage. Ke4-TIB may have a potential of in vivo X-ray imaging in animal arthritic models in future, which contribute to drug discovery research for osteoarthritis.

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  • Creation and evaluation of RXR partial agonists for the substitutes of steroidal anti-inflammatory agents

    Grant number：22790108  2010 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAKUTA Hiroki

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    Grant amount：\3900000 （ Direct expense: \3000000 、 Indirect expense：\900000 ）

    Effective substitutes of steroidal anti-inflammatory agents for the treatment of allergies and inflammation are required. Thus, we aimed to create new non-steroidal anti-inflammatory agents by targeting retinoid x receptors. By structural development of NEt-3IB(6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl) amino] nicotinic acid), a potent RXR agonist, several RXR partial agonists were found. Among them, NEt-4IB(6-[N-ethyl-N-(4-isobutoxy-3-isopropylphenyl) amino] nicotinic acid) was found as a new orally available RXR partial agonist. In addition, this compound showed potent anti-inflammatory activity against the TPA induced skin inflammation without significant side effects.

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  • Creation of drug candidates for the treatment of inflammatory orphan disease

    Grant number：20790101  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KAKUTA Hiroki

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    Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）

    The objective of this research is to produce new compounds effective against inflammatory orphan diseases including inflammatory bowel disease or Crohn disease. Production of new anti-inflammatory compounds was performed by targeting nuclear receptors, retinoid X receptors (RXRs) and retinoic acid receptors (RARs).As a result, RXR agonists were found to show anti-inflammatory activity against DSS-induced and TNBS induced mice colitis.

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  • 細胞分化を制御する複素環化合物の創製

    Grant number：17790090  2005 - 2006

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    加来田 博貴

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    Grant amount：\3200000 （ Direct expense: \3200000 ）

    本研究では、細胞分化に関与する核内受容体の一つであるレチノイドX受容体RXRアゴニスト活性を有する複素環化合物の開発を主に展開した。
    新規RXRアゴニストを開発するにあたり、その構造的バリエーションの少なさ、脂溶性の高さ、α・β・γと3つあるサブタイプに対する特異的なリガンドが報告されていないことに着目し、これらを解決課題とした。
    一般的なRXRアゴニストは、テトラメチルテトラヒドロナフチル環からなる疎水性部位と芳香族カルボン酸等の極性部位、それとこれら二つの部位を連結するリンカー部分から構成される。そこで、リンカー部分に脂溶性低下の期待できるスルホンアミド基の導入、テトラメチルテトラヒドロナフチル環をイソプロピル基と極性のあるアルコキシ基を有する芳香環への変換、さらに芳香族カルボン酸のカルボキシル基をアクリル酸への変換という3つのアプローチから分子デザインした。
    合成化合物のRXRリガンド活性については、COS-1細胞を用いたreporter gene assayを用いて評価した。その結果、アルコキシル基の導入を図った化合物について、低脂溶性でありながら既存の高活性アゴニストに匹敵するRXRアゴニスト活性およびRXRα選択性が認められた。なお、サブタイプ選択的RXRアゴニストの報告例がないことから、本化合物は世界初のRXRサブタイプ選択的アゴニストと言える。またアクリル酸を導入した化合物にRXRアゴニスト作用のみならず、HDAC阻害作用を有する化合物も見出した。以上の化合物については、特許出願(特願2007-48059)しており、現在文献化中である。
    RXRアゴニストは、タモキシフェン耐性乳がんやタキソール耐性がん、II型糖尿病の治療の他、がん化学予防、発毛作用についても研究されている。したがって、本研究で開発されたRXRアゴニストは、これらへの応用が可能と考えている。

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  • 第62回 日本生化学会 中国・四国支部例会　実行委員（事務局長）

    2021.09

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    岡山大学 学術研究院 環境生命科学学域（農学系）木村吉伸教授を実行委員長とする本支部例会をzoom webinarにて開催した。加来田は、その運営を取りまとめる事務局を担当し、当該例会案内ポスター、webサイト、発表要旨等の作成、当日の運営を務めた。

 

Class subject in charge

  • Advanced Seminars in Drug Discovery and Drug Development (Clinical information for drug development) （2024academic year） special  - その他

  • Medicinal Sciences （2024academic year） Second semester  - 金5～6

  • Medicinal Sciences （2024academic year） Third semester  - 金5～6

  • Seminar on intellectual property in drug development （2024academic year） special  - その他

  • Experimental Organic Chemistry （2024academic year） 1st and 2nd semester  - その他5～9

  • Experimental Organic Chemistry （2024academic year） 1st and 2nd semester  - その他5～9

  • Medicinal Chemistry （2024academic year） 1st and 2nd semester  - [第１学期]火3～4, [第２学期]木2～4

  • Medicinal Chemistry （2024academic year） 1st and 2nd semester  - [第１学期]火3～4, [第２学期]木2～4

  • Synthetic Medicinal Chemistry 1 （2024academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 1 （2024academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 2 （2024academic year） Second semester  - 木2～4

  • Synthetic Medicinal Chemistry 2 （2024academic year） Second semester  - 木2～4

  • Clinical information for drug development （2024academic year） special  - その他

  • Clinical information for drug development （2024academic year） special  - その他

  • Advanced Lectures: Development of Chemical Medicines （2024academic year） special  - その他

  • Development of Chemical Medicines I （2024academic year） special  - その他

  • Development of Chemical Medicines II （2024academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2024academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2024academic year） special  - その他

  • Next Generation Drugs （2024academic year） Third semester  - 木1～2

  • bioorganic chemistry （2024academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2024academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2024academic year） Second semester  - 水1～2

  • bioorganic chemistry （2024academic year） Second semester  - 水1～2

  • Practice in Fundamental Pharmaceutical Sciences II （2024academic year） 1st and 2nd semester  - その他5～9

  • Practice in Fundamental Pharmaceutical Sciences II （2024academic year） 1st and 2nd semester  - その他5～9

  • Advanced Seminars in Drug Discovery and Drug Development (Clinical information for drug development) （2023academic year） special  - その他

  • Medicinal Sciences （2023academic year） Second semester  - 金5～6

  • Medicinal Sciences （2023academic year） Third semester  - 金5～6

  • Seminar on intellectual property in drug development （2023academic year） special  - その他

  • Experimental Organic Chemistry （2023academic year） 1st and 2nd semester  - その他5～9

  • Experimental Organic Chemistry （2023academic year） 1st and 2nd semester  - その他5～9

  • Medicinal Chemistry （2023academic year） 1st and 2nd semester  - [第１学期]火3～4, [第２学期]木2～4

  • Medicinal Chemistry （2023academic year） 1st and 2nd semester  - [第１学期]火3～4, [第２学期]木2～4

  • Synthetic Medicinal Chemistry 1 （2023academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 1 （2023academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 2 （2023academic year） Second semester  - 木2～4

  • Synthetic Medicinal Chemistry 2 （2023academic year） Second semester  - 木2～4

  • Clinical information for drug development （2023academic year） special  - その他

  • Clinical information for drug development （2023academic year） special  - その他

  • Advanced Lectures: Development of Chemical Medicines （2023academic year） special  - その他

  • Development of Chemical Medicines I （2023academic year） special  - その他

  • Development of Chemical Medicines II （2023academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2023academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2023academic year） special  - その他

  • bioorganic chemistry （2023academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2023academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2023academic year） Second semester  - 水1～2

  • bioorganic chemistry （2023academic year） Second semester  - 水1～2

  • Practice in Fundamental Pharmaceutical Sciences II （2023academic year） 1st and 2nd semester  - その他5～9

  • Practice in Fundamental Pharmaceutical Sciences II （2023academic year） 1st and 2nd semester  - その他5～9

  • Medicinal Sciences （2022academic year） Second semester  - 金5～6

  • Medicinal Sciences （2022academic year） Third semester  - 金5～6

  • Seminar on intellectual property in drug development （2022academic year） special  - その他

  • Synthetic Medicinal Chemistry 1 （2022academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 1 （2022academic year） 1st semester  - 火3～4

  • Synthetic Medicinal Chemistry 2 （2022academic year） Second semester  - 木1～2

  • Synthetic Medicinal Chemistry 2 （2022academic year） Second semester  - 木1～2

  • Clinical information for drug development （2022academic year） special  - その他

  • Development of Synthetic Drug I （2022academic year） special  - その他

  • Development of Synthetic Drug II （2022academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2022academic year） special  - その他

  • bioorganic chemistry （2022academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2022academic year） Second semester  - 水1～2

  • Bioorganic Chemistry （2022academic year） Second semester  - 水1～2

  • bioorganic chemistry （2022academic year） Second semester  - 水1～2

  • Practice in Fundamental Pharmaceutical Sciences II （2022academic year） 1st and 2nd semester  - その他5～9

  • Practice in Fundamental Pharmaceutical Sciences II （2022academic year） 1st and 2nd semester  - その他5～9

  • Scientific Backgrounds of Medicines （2021academic year） Second semester  - 木1～2

  • Medicinal Sciences （2021academic year） Second semester  - 金5～6

  • Medicinal Sciences （2021academic year） Third semester  - 金5～6

  • Seminar on intellectual property in drug development （2021academic year） special  - その他

  • Synthetic Medicinal Chemistry 1 （2021academic year） 1st semester  - 火1,火2

  • Synthetic Medicinal Chemistry 2 （2021academic year） Second semester  - 火1,火2

  • Clinical information for drug development （2021academic year） special  - その他

  • Development of Synthetic Drug I （2021academic year） special  - その他

  • Development of Synthetic Drug II （2021academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2021academic year） Late  - その他

  • bioorganic chemistry （2021academic year） Second semester  - 水1,水2

  • Practice in Fundamental Pharmaceutical Sciences II （2021academic year） 1st and 2nd semester  - その他6～9

  • Seminar on intellectual property in drug development （2020academic year） special  - その他

  • Chemistry a La Carte （2020academic year） 1st semester  - 月1,月2

  • Synthetic Medicinal Chemistry 1 （2020academic year） 1st semester  - 火1,火2

  • Synthetic Medicinal Chemistry 2 （2020academic year） Second semester  - 火1,火2

  • Synthetic Medicinal Chemistry I （2020academic year） 1st and 2nd semester  - 火1,火2

  • Synthetic Medicinal Chemistry I （2020academic year） 3rd and 4th semester  - 水5,水6

  • Clinical information for drug development （2020academic year） special  - その他

  • Development of Synthetic Drug I （2020academic year） special  - その他

  • Development of Synthetic Drug II （2020academic year） special  - その他

  • Organic Chemistry and Natural Products Chemistry （2020academic year） special  - その他

  • bioorganic chemistry （2020academic year） Second semester  - 水1,水2

  • Practice in Fundamental Pharmaceutical Sciences II （2020academic year） special  - その他

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Social Activities

  • 岡山大学薬友会　運営教員

    Role(s)：Organizing member

    2021.4.1

Media Coverage

  • 悪性リンパ腫治療薬「bexarotene(ベキサロテン)」のラット胎児奇形や胎児移行性を明らかに〜催奇形性を軽減した新たな創薬に期待〜 Internet

    岡山大学プレスリリース  https://www.okayama-u.ac.jp/tp/release/release_id1008.html  2022.9

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    Author：Myself 

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  • Hope for inflammatory bowel disease with novel “green” synthesis of drug candidate Internet

    EurekAlert!  https://www.eurekalert.org/news-releases/945672  2022.3

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  • Developing an environmentally friendly mass synthetic method for NEt-3IB candidates for inflammatory bowel diseases ～From the perspective of contributing to SDGs by reducing the volume of waste liquid in synthesizing drug substances～ Internet

    http://www.okayama-u.ac.jp/eng/research_highlights/index_id154.html  2022.2

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Academic Activities

  • Review: Journal of Medicinal Chemistry

    Role(s)：Review, evaluation

    2021.12.18

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    Type：Peer review 

  • Review: Bioorganic & Medicinal Chemistry Letters

    Role(s)：Review, evaluation

    2021.11.7

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    Type：Peer review 

  • Review: Journal of Medicinal Chemistry

    Role(s)：Review, evaluation

    2021.9.2

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    Type：Peer review 

  • Review: Bioorganic & Medicinal Chemistry Letters

    Role(s)：Review, evaluation

    2021.7.15

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    Type：Peer review 

  • Review: ACS Omega

    Role(s)：Review, evaluation

    2021.6.16

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    Type：Peer review 

  • Review: Bioorganic & Medicinal Chemistry Letters

    Role(s)：Review, evaluation

    2021.4.17

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    Type：Peer review 

  • Review: BBA - Molecular Cell Research

    Role(s)：Review, evaluation

    2021.2.26

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    Type：Peer review 

  • Review: Bioorganic & Medicinal Chemistry Letters

    Role(s)：Review, evaluation

    2021.1.23

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    Type：Peer review 

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