研究者詳細 - 加来田　博貴

論文 - 加来田　博貴

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3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity 査読国際誌

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

Bioorganic & Medicinal Chemistry Letters 29 ( 15 ) 1891 - 1894 2019年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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.

DOI： 10.1016/j.bmcl.2019.05.050

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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 査読

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年5月

Fluorine-18 (¹⁸F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands. 査読国際誌

Takamura Y, Shibahara O, Watanabe M, Fujihara M, Yamada S, Akehi M, Sasaki T, Hirano H, Kakuta H

Bioorganic & medicinal chemistry 27 ( 14 ) 3128 - 3134 2019年5月

A partial agonist for retinoid X receptor mitigates experimental colitis. 査読国際誌

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年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1093/intimm/dxy089

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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年3月

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. 査読国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1186/s12931-018-0963-0

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Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα). 査読国際誌

Miyashita Y, Numoto N, Arulmozhiraja S, Nakano S, Matsuo N, Shimizu K, Shibahara O, Fujihara M, Kakuta H, Ito S, Ikura T, Ito N, Tokiwa H

FEBS letters 593 ( 2 ) 242 - 250 2019年1月

Problems with laboratory notebooks in academia and how to resolve them

Kakuta, H.

Yakugaku Zasshi 139 ( 6 ) 2019年

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年

Retinoid X Receptor Antagonists

Masaki Watanabe, Hiroki Kakuta

International Journal of Molecular Sciences 19 ( 8 ) 2354 - 2354 2018年8月

Retinoid X Receptor Antagonists

Hiroki Kakuta

International Journal of Molecular Sciences 2018年8月

Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer 査読国際誌

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年

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1158/1078-0432.ccr-18-0982

DOI： 10.1158/1078-0432.CCR-18-0982

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Retinoid X receptor antagonists

Watanabe, M., Kakuta, H.

International Journal of Molecular Sciences 19 ( 8 ) 2018年

Retinoid X Receptor Antagonists

Hiroki Kakuta

International journal of molecular sciences 2018年

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 Imagin・・・査読国際誌

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年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1021/acs.jmedchem.7b00817

Web of Science

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Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma. 査読国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1186/s12931-017-0507-z

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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 査読

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年

Retinoid X Receptor Ligands with Anti-Type 2 Diabetic Activity

Hiroki Kakuta

Current topics in medicinal chemistry 2017年

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

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年

Retinoid x receptor ligands with anti-type 2 diabetic activity

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

Current Topics in Medicinal Chemistry 16 ( 30 ) 2016年

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