顔写真

イシカワ ミノル
石川 稔
Minoru Ishikawa
所属
大学院生命科学研究科 分子化学生物学専攻 ケミカルバイオロジー講座(活性分子動態分野)
職名
教授
学位
  • 博士(薬学)(東京大学)

  • 修士(工学)(東京工業大学)

経歴 9

  • 2019年4月 ~ 継続中
    東北大学 大学院生命科学研究科 教授

  • 2019年 ~ 2021年
    理化学研究所 客員研究員(兼務)

  • 2018年4月 ~ 2019年3月
    東京大学 定量生命科学研究所 准教授

  • 2013年4月 ~ 2018年3月
    東京大学 分子細胞生物学研究所 准教授

  • 2014年4月 ~ 2015年3月
    東京大学 大学院農学系研究科 非常勤講師(兼務)

  • 2012年10月 ~ 2013年3月
    東京大学 分子細胞生物学研究所 講師

  • 2008年7月 ~ 2012年9月
    東京大学 分子細胞生物学研究所 助教

  • 1996年4月 ~ 2008年6月
    明治製菓株式会社(現Meiji Seikaファルマ株式会社) 創薬研究所 研究員

  • 2021年 ~
    東京大学 大学院薬学系研究科 非常勤講師(兼務)

︎全件表示 ︎最初の5件までを表示

学歴 3

  • 東京工業大学 大学院生命理工学研究科 バイオテクノロジー専攻

    1994年4月 ~ 1996年3月

  • 東京工業大学 生命理工学部 生体分子工学科

    1991年4月 ~ 1994年3月

  • 東京工業大学 第3類

    1990年4月 ~ 1991年3月

委員歴 17

  • 有機合成化学協会 「ニューモダリティと有機合成化学」研究部会幹事

    2022年 ~ 継続中

  • American Chemical Society Journal of Medicinal Chemistry Editorial Advisory Board

    2020年 ~ 継続中

  • 日本薬学会医薬化学部会 創薬ニューフロンティア検討会 委員

    2018年4月 ~ 継続中

  • 日本薬学会医薬化学部会 MEDCHEM NEWS編集委員

    2017年4月 ~ 継続中

  • 日本学術振興会 科学研究費委員会専門委員

    2015年4月 ~ 2017年3月

  • 日本薬学会 ファルマシアトピックス小委員

    2007年4月 ~ 2010年3月

  • 有機合成化学協会東北支部 常任幹事

    2020年 ~ 継続中

  • 日本薬学会医薬化学部会 第39回メディシナルケミストリーシンポジウム実行委員

    2022年 ~

  • 日本農芸化学会 日本農芸化学会2021年度大会 実行委員

    2021年 ~

  • 日本薬学会 医薬化学部会 第38回メディシナルケミストリーシンポジウム実行委員

    2020年 ~

  • The Fourth A3 Roundtable Meeting on Asia Chemical Probe Research Hub実行委員

    2019年 ~

  • 日本化学会生体機能関連化学部会・日本化学会バイオテクノロジー部会 第13回バイオ関連化学シンポジウム実行委員

    2019年 ~

  • 日本薬学会医薬化学部会 第37回メディシナルケミストリーシンポジウム実行委員

    2019年 ~

  • 日本薬学会 代議員(関東支部)

    2019年 ~

  • 日本化学会医農薬化学ディビジョン アジア国際シンポジウム実行委員

    2014年 ~

  • 日本薬学会医薬化学部会 第28回メディシナルケミストリーシンポジウム 世話人

    2009年 ~

  • 日本薬学会 第128年会 組織委員会プログラム委員

    2008年 ~

︎全件表示 ︎最初の5件までを表示

所属学協会 8

  • 日本化学会

  • 日本ケミカルバイオロジー学会

  • 日本薬学会医薬化学部会

  • 日本農芸化学会

  • 日本レチノイド研究会

  • American chemical society

  • 有機合成化学協会

  • 日本薬学会

︎全件表示 ︎最初の5件までを表示

研究キーワード 8

  • 水溶性

  • ユビキチン

  • druglike

  • 核内受容体

  • タンパク質分解

  • 生物有機化学

  • ケミカルバイオロジー

  • 創薬化学

研究分野 3

  • ナノテク・材料 / ケミカルバイオロジー /

  • ナノテク・材料 / 生体化学 /

  • ライフサイエンス / 薬系化学、創薬科学 /

受賞 9

  1. 2023年度日本薬学会メディシナルケミストリーシンポジウム優秀賞

    2023年11月 日本薬学会医薬化学部会

  2. 平成29年度日本薬学会医薬化学部会メディシナルケミストリーシンポジウム優秀賞

    2017年10月 日本薬学会医薬化学部会

  3. レチノイド研究会第26回学術集会奨励賞(首藤賞)

    2015年10月 レチノイド研究会

  4. 10th AFMC International Medicinal Chemistry Symposium (AIMECS2015) Poster Presentation Prize

    2015年10月

  5. Journal of Medicinal Chemistry Highly Cited Perspective of 2011

    2013年2月 American Chemical Society

  6. Journal of Medicinal Chemistry Highly Read Perspective of 2011

    2013年2月 American Chemical Society

  7. 2010年度(第23回)有機合成化学協会研究企画賞 (武田薬品工業研究企画賞)

    2011年2月 有機合成化学協会

  8. 薬品総合研究所所長賞

    2001年 明治製菓株式会社

  9. 第8回日本薬学会医薬化学部会年会ポスター賞

    1999年11月 日本薬学会医薬化学部会

︎全件表示 ︎最初の5件までを表示

論文 83

  1. Allosteric Hsp70 Modulator YM-1 Induces Degradation of BRD4 国際誌 招待有り 査読有り

    Yugo Mishima, Shusuke Tomoshige, Shinichi Sato, Minoru Ishikawa

    Chemical and Pharmaceutical Bulletin 72 (2) 161-165 2024年2月1日

    DOI: 10.1248/cpb.c23-00543  

  2. 標的タンパク質分解薬PROTAC 招待有り 査読有り

    石川稔, 友重秀介

    PEPTIDE NEWSLETTER JAPAN 128 7-10 2023年4月

  3. Near-Infrared-Light-Activatable Proximity Labeling of Bead-Binding Proteins

    Shinichi Sato, Keita Nakane, Yuki Hoshino, Kosuke Dodo, Shusuke Tomoshige, Minoru Ishikawa, Taniyuki Furuyama

    2023年3月21日

    出版者・発行元:American Chemical Society (ACS)

    DOI: 10.26434/chemrxiv-2023-443cj  

    詳細を見る 詳細を閉じる

    Photocatalytic proximity labeling has recently undergone significant advances as a valuable tool for understanding protein–protein and cell–cell interactions. This paper reports the first photocatalytic protein-labeling approach in which the reaction can be controlled using near-infrared (NIR) light (810 nm). Magnetic affinity beads with encapsulated sulfur-substituted silicon (IV) phthalocyanine, which produces singlet oxygen upon NIR irradiation, were prepared. We have developed a method in which the histidine residues of proteins bound to the ligands on the beads are selectively oxidized and labeled by the nucleophilic labeling reagent while minimizing nonspecific adsorption to the dye. Beads with aryl sulfamide, lactose, or CZC-8004 ligands immobilized on their surface can be used to label proteins that bind these ligands, as well as their protein–protein interaction partners.

  4. Switching of Photocatalytic Tyrosine/Histidine Labeling and Application to Photocatalytic Proximity Labeling

    Keita Nakane, Haruto Nagasawa, Chizu Fujimura, Eri Koyanagi, Shusuke Tomoshige, Minoru Ishikawa, Shinichi Sato

    International Journal of Molecular Sciences 23 (19) 11622-11622 2022年10月2日

    出版者・発行元:MDPI AG

    DOI: 10.3390/ijms231911622  

    eISSN:1422-0067

    詳細を見る 詳細を閉じる

    Weak and transient protein interactions are involved in dynamic biological responses and are an important research subject; however, methods to elucidate such interactions are lacking. Proximity labeling is a promising technique for labeling transient ligand–binding proteins and protein–protein interaction partners of analytes via an irreversible covalent bond. Expanding chemical tools for proximity labeling is required to analyze the interactome. We developed several photocatalytic proximity-labeling reactions mediated by two different mechanisms. We found that numerous dye molecules can function as catalysts for protein labeling. We also identified catalysts that selectively modify tyrosine and histidine residues and evaluated their mechanisms. Model experiments using HaloTag were performed to demonstrate photocatalytic proximity labeling. We found that both ATTO465, which catalyzes labeling by a single electron transfer, and BODIPY, which catalyzes labeling by singlet oxygen, catalyze proximity labeling in cells.

  5. 標的タンパク質分解薬による創薬パラダイムシフト -低分子リガンドの活躍 招待有り

    友重秀介, 石川稔

    月刊細胞 54 (9) 504-507 2022年7月

  6. 分子間相互作用低下による生物活性物質の水溶性向上策 招待有り 査読有り

    石川稔

    YAKUGAKU ZASSHI 142 (4) 365-379 2022年4月

    出版者・発行元:None

    DOI: 10.1248/yakushi.21-00185-3  

    ISSN:0031-6903

    eISSN:1347-5231

  7. Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties 国際誌 査読有り

    Keigo Hirai, Hiroko Yamashita, Shusuke Tomoshige, Yugo Mishima, Tatsuya Niwa, Kenji Ohgane, Mayumi Ishii, Kayoko Kanamitsu, Yui Ikemi, Shinsaku Nakagawa, Hideki Taguchi, Shinichi Sato, Yuichi Hashimoto, Minoru Ishikawa

    ACS Medicinal Chemistry Letters 13 (3) 396-402 2022年3月

    出版者・発行元:American Chemical Society (ACS)

    DOI: 10.1021/acsmedchemlett.1c00500  

    ISSN:1948-5875

    eISSN:1948-5875

    詳細を見る 詳細を閉じる

    The onset of neurodegenerative disorders (NDs), such as Alzheimer's disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.

  8. BODIPY Catalyzes Proximity‐Dependent Histidine Labelling 査読有り

    Keita Nakane, Tatsuya Niwa, Michihiko Tsushima, Shusuke Tomoshige, Hideki Taguchi, Hiroyuki Nakamura, Minoru Ishikawa, Shinichi Sato

    ChemCatChem 14 (9) 2022年2月20日

    出版者・発行元:Wiley

    DOI: 10.1002/cctc.202200077  

    ISSN:1867-3880

    eISSN:1867-3899

  9. Functionalization of Human Serum Albumin by Tyrosine Click 査読有り

    Satsuki Obara, Keita Nakane, Chizu Fujimura, Shusuke Tomoshige, Minoru Ishikawa, Shinichi Sato

    International Journal of Molecular Sciences 22 (16) 8676-8676 2021年8月

    出版者・発行元:MDPI AG

    DOI: 10.3390/ijms22168676  

    eISSN:1422-0067

    詳細を見る 詳細を閉じる

    Human serum albumin (HSA) is a promising drug delivery carrier. Although covalent modification of Cys34 is a well-established method, it is desirable to develop a novel covalent modification method that targets residues other than cysteine to introduce multiple functions into a single HSA molecule. We developed a tyrosine-selective modification of HSA. Three tyrosine selective modification methods, hemin-catalyzed, horseradish peroxidase (HRP)-catalyzed, and laccase-catalyzed reactions were performed, and the modification efficiencies and modification sites of the modified HSAs obtained by these methods were evaluated and compared. We found that the laccase-catalyzed method could efficiently modify the tyrosine residue of HSA under mild reaction conditions without inducing oxidative side reactions. An average of 2.2 molecules of functional groups could be introduced to a single molecule of HSA by the laccase method. Binding site analysis using mass spectrometry suggested Y84, Y138, and Y401 as the main modification sites. Furthermore, we evaluated binding to ibuprofen and found that, unlike the conventional lysine residue modification, the inhibition of drug binding was minimal. These results suggest that tyrosine-residue selective chemical modification is a promising method for covalent drug attachment to HSA.

  10. 医薬リード化合物の体内動態改善法 –水溶性・脂溶性のアウフヘーベン– 招待有り 査読有り

    石川稔

    ファルマシア 57 620-624 2021年7月

  11. Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog 査読有り

    Junki Morimoto, Kazunori Miyamoto, Yuki Ichikawa, Masanobu Uchiyama, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

    Scientific Reports 11 12697 2021年6月

  12. Proximity Histidine Labeling by Umpolung Strategy Using Singlet Oxygen 国際誌 査読有り

    Keita Nakane, Shinichi Sato, Tatsuya Niwa, Michihiko Tsushima, Shusuke Tomoshige, Hideki Taguchi, Minoru Ishikawa, Hiroyuki Nakamura

    Journal of the American Chemical Society 143 (20) 7726-7731 2021年5月26日

    出版者・発行元:American Chemical Society (ACS)

    DOI: 10.1021/jacs.1c01626  

    ISSN:0002-7863

    eISSN:1520-5126

    詳細を見る 詳細を閉じる

    While electrophilic reagents for histidine labeling have been developed, we report an umpolung strategy for histidine functionalization. A nucleophilic small molecule, 1-methyl-4-arylurazole, selectively labeled histidine under singlet oxygen (1O2) generation conditions. Rapid histidine labeling can be applied for instant protein labeling. Utilizing the short diffusion distance of 1O2 and a technique to localize the 1O2 generator, a photocatalyst in close proximity to the ligand-binding site, we demonstrated antibody Fc-selective labeling on magnetic beads functionalized with a ruthenium photocatalyst and Fc ligand, ApA. Three histidine residues located around the ApA binding site were identified as labeling sites by liquid chromatography-mass spectrometry analysis. This result suggests that 1O2-mediated histidine labeling can be applied to a proximity labeling reaction on the nanometer scale.

  13. In Vivo Synthetic Chemistry of Proteolysis Targeting Chimeras (PROTACs) 招待有り 査読有り

    Shusuke Tomoshige, Minoru Ishikawa

    Bioorganic & Medicinal Chemistry 41 116221-116221 2021年5月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2021.116221  

    ISSN:0968-0896

  14. PROTACs and Other Chemical Protein Degradation Technologies for the Treatment of Neurodegenerative Disorders 査読有り

    Shusuke Tomoshige, Minoru Ishikawa

    Angewandte Chemie International Edition 60 3346-3354 2021年2月

    出版者・発行元:Wiley

    DOI: 10.1002/anie.202004746  

    ISSN:1433-7851

    eISSN:1521-3773

  15. meta-Non-flat substituents: a novel molecular design to improve aqueous solubility in small molecule drug discovery 国際誌 査読有り

    Yuki Ichikawa, Michiaki Hiramatsu, Yusuke Mita, Makoto Makishima, Yotaro Matsumoto, Yui Masumoto, Atsuya Muranaka, Masanobu Uchiyama, Yuichi Hashimoto, Minoru Ishikawa

    Organic & Biomolecular Chemistry 19 (2) 446-456 2021年1月

    出版者・発行元:Royal Society of Chemistry (RSC)

    DOI: 10.1039/d0ob02083d  

    ISSN:1477-0520

    eISSN:1477-0539

    詳細を見る 詳細を閉じる

    <p>We found a novel molecular design for improvement in the aqueous solubility of small molecule drugs.</p>

  16. Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs 査読有り

    Ryuta Shioi, Fumika Karaki, Hiromasa Yoshioka, Tomomi Noguchi-Yachide, Minoru Ishikawa, Kosuke Dodo, Yuichi Hashimoto, Mikiko Sodeoka, Kenji Ohgane

    PLoS ONE 15 (12) e0243746-e0243746 2020年12月

    出版者・発行元:None

    DOI: 10.1371/journal.pone.0243746  

    eISSN:1932-6203

  17. 神経変性疾患治療に向けたタンパク質分解アプローチ 招待有り 査読有り

    友重秀介、石川稔

    実験医学 38 (14) 2326-2330 2020年8月

  18. 疾患疾患原因タンパク質の寿命を短縮する分子の創製と医薬応用への課題 招待有り 査読有り

    石川稔

    Drug Delivery System 35 (3) 229-239 2020年7月

  19. 生細胞内の疾患関連タンパク質を 減少させる低分子創薬手法の開発 招待有り 査読有り

    石川稔, 橋本祐一

    有機合成化学協会誌 78 (5) 402-413 2020年5月

  20. Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs. 国際誌 査読有り

    Minoru Ishikawa, Shusuke Tomoshige, Yosuke Demizu, Mikihiko Naito

    Pharmaceuticals (Basel, Switzerland) 13 (4) 74 2020年4月21日

    DOI: 10.3390/ph13040074  

    詳細を見る 詳細を閉じる

    New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation. We cover strategies for increasing the degradation activity induced by small molecules, and their scope for application to undruggable proteins.

  21. Application of Protein Knockdown Strategy Targeting β-Sheet Structure to Multiple Disease-associated Polyglutamine Proteins 国際誌 査読有り

    Hiroko Yamashita, Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa

    Bioorganic & Medicinal Chemistry 28 (1) 115175-115175 2020年

    DOI: 10.1016/j.bmc.2019.115175  

  22. Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton 査読有り

    Yuko Nishiyama, Shinya Fujii, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

    International Journal of Molecular Sciences 2018年7月

    DOI: 10.3390/ijms19072090  

  23. Structural development of tetrachlorophthalimides as liver X receptor β (LXRβ)-selective agonists with improved aqueous solubility 査読有り

    Nomura S, Endo-Umeda K, Fujii S, Makishima M, Hashimoto Y, Ishikawa M

    Bioorganic and Medicinal Chemistry Letters 28 (4) 796-801 2018年2月15日

    出版者・発行元:None

    DOI: 10.1016/j.bmcl.2017.12.024  

    ISSN:1464-3405 0960-894X

  24. Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative 査読有り

    Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa

    Bioorganic and Medicinal Chemistry Letters 28 (4) 707-710 2018年2月15日

    出版者・発行元:Elsevier Ltd

    DOI: 10.1016/j.bmcl.2018.01.012  

    ISSN:1464-3405 0960-894X

    詳細を見る 詳細を閉じる

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy.

  25. 神経変性疾患原因タンパク質のケミカルノックダウン 招待有り

    石川稔, 友重秀介, 野村さやか, 山下博子, 大金賢司

    MEDCHEM NEWS 28 88-92 2018年

  26. Unexpected emergence of luciferase-inhibitory activity during structural development study of phenyloxadiazole-based PPAR ligands 査読有り

    Shioi R, Toyota Y, Noguchi-Yachide T, Ishikawa M, Yamaguchi T, Makishima M, Hashimoto Y, Ohgane K

    Heterocycles 97 (2) 854-864 2018年

  27. Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton 査読有り

    Nishiyama Y, Mori S, Makishima M, Fujii S, Kagechika H, Hashimoto Y, Ishikawa M

    ACS Medicinal Chemistry Letters 9 (7) 641-645 2018年

    DOI: 10.1021/acsmedchemlett.8b00058  

  28. Photo-enhanced Aqueous Solubilization of an Azo-compound 査読有り

    Minoru Ishikawa, Takuya Ohzono, Takao Yamaguchi, Yasuo Norikane

    Scientific Reports 7 6909 2017年12月1日

    出版者・発行元:Nature Publishing Group

    DOI: 10.1038/s41598-017-06947-w  

    ISSN:2045-2322

    詳細を見る 詳細を閉じる

    We previously showed that disruption of intermolecular interactions, e.g., by lowering the molecular planarity and/or introducing bent structures, improves the aqueous solubility of compounds, and based upon that work, we hypothesized that azobenzene trans-to-cis photoswitching could also be utilized to enhance the aqueous solubility of compounds. Here, we demonstrate that UV/visible light irradiation can reversibly switch the aqueous solubilization of an anti-cancer candidate drug, a low-molecular-weight kinase inhibitor bearing an azobenzene moiety. The increase of solubilization associated with UV-induced trans-to-cis conversion may have clinical relevance, because the time-scale of thermal cis-to-trans reversion at 37 °C is longer than that of oral absorption.

  29. Structural development studies of pyrazoloketone-derived acetyl-CoA carboxylase inhibitors 査読有り

    Shogo Okazaki, Taki Sakai, Minoru Ishikawa, Yuichi Hashimoto, Takao Yamaguchi

    Heterocycles 2017年12月

  30. Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30. 国際誌 査読有り

    Yusuke Sato, Kei Okatsu, Yasushi Saeki, Koji Yamano, Noriyuki Matsuda, Ai Kaiho, Atsushi Yamagata, Sakurako Goto-Ito, Minoru Ishikawa, Yuichi Hashimoto, Keiji Tanaka, Shuya Fukai

    Nature structural & molecular biology 24 (11) 911-919 2017年11月

    DOI: 10.1038/nsmb.3469  

    詳細を見る 詳細を閉じる

    Parkin ubiquitin (Ub) ligase (also known as PARK2) ubiquitinates damaged mitochondria for their clearance and quality control. USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. Here, we report the crystal structure of zebrafish USP30 in complex with a Lys6-linked diubiquitin (diUb or Ub2) at 1.87-Å resolution. The distal Ub-recognition mechanism of USP30 is similar to those of other USP family members, whereas Phe4 and Thr12 of the proximal Ub are recognized by a USP30-specific surface. Structure-based mutagenesis showed that the interface with the proximal Ub is critical for the specific cleavage of Lys6-linked Ub chains, together with the noncanonical catalytic triad composed of Cys-His-Ser. The structural findings presented here reveal a mechanism for Lys6-linkage-specific deubiquitination.

  31. Discovery of Small Molecules that Induce the Degradation of Huntingtin 査読有り

    Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 56 (38) 11530-11533 2017年9月

    出版者・発行元:WILEY-V C H VERLAG GMBH

    DOI: 10.1002/anie.201706529  

    ISSN:1433-7851

    eISSN:1521-3773

    詳細を見る 詳細を閉じる

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective therapeutic approach. We designed two small hybrid molecules (1 and 2) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin-proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD.

  32. 1α-Hydroxy derivatives of 7-dehydrocholesterol are selective liver X receptor modulators 査読有り

    Endo-Umeda K, Aoyama A, Shimizu M, Ishikawa M, Hashimoto Y, Yamada S, Makishima M

    Journal of Steroid Biochemistry and Molecular Biology 172 136-148 2017年9月

    出版者・発行元:None

    DOI: 10.1016/j.jsbmb.2017.07.014  

    ISSN:0960-0760

  33. Specific fluorescence labeling of target proteins by using a ligand-4-azidophthalimide conjugate 査読有り

    Kosuke Chiba, Miwako Asanuma, Minoru Ishikawa, Yuichi Hashimoto, Kosuke Dodo, Mikiko Sodeoka, Takao Yamaguchi

    CHEMICAL COMMUNICATIONS 53 (62) 8751-8754 2017年8月

    出版者・発行元:ROYAL SOC CHEMISTRY

    DOI: 10.1039/c7cc03252h  

    ISSN:1359-7345

    eISSN:1364-548X

    詳細を見る 詳細を閉じる

    We herein propose a simple affinity-labeling method using a ligand-4-azidophthalimide (AzPI) conjugate. As a proof of concept, we show that two different ligand-AzPI conjugates enabled highly specific fluorescence labeling of their individual target proteins even in crude cell lysates. This method was also applied to label endogenous target proteins inside living cells.

  34. Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists 査読有り

    Shioi R, Okazaki S, Noguchi-Yachide T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T

    Bioorganic and Medicinal Chemistry Letters 27 (14) 3131-3134 2017年7月

    出版者・発行元:None

    DOI: 10.1016/j.bmcl.2017.05.037  

    ISSN:0960-894X

    eISSN:1464-3405

  35. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression 査読有り

    Yosuke Toyota, Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 (12) 2776-2780 2017年6月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2017.04.061  

    ISSN:0960-894X

    eISSN:1464-3405

    詳細を見る 詳細を閉じる

    Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRA gamma) ligands are thought to be largely due to PPAR gamma-mediated transrepression. Thus, transrepression-selective PPAR gamma ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPAR gamma agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC50: 14 mu M) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. (C) 2017 Elsevier Ltd. All rights reserved.

  36. Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein 査読有り

    Hiromitsu Fukuda, Fumika Karaki, Kosuke Dodo, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto, Kenji Ohgane

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 (12) 2781-2787 2017年6月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2017.04.062  

    ISSN:0960-894X

    eISSN:1464-3405

    詳細を見る 詳細を閉じる

    Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships. (C) 2017 Elsevier Ltd. All rights reserved.

  37. Targeted degradation of proteins localized in subcellular compartments by hybrid small molecules 査読有り

    Keiichiro Okuhira, Takuji Shoda, Risa Omura, Nobumichi Ohoka, Takayuki Hattori, Norihito Shibata, Yosuke Demizu, Ryo Sugihara, Asato Ichino, Haruka Kawahara, Yukihiro Itoh, Minoru Ishikawa, Yuichi Hashimoto, Masaaki Kurihara, Susumu Itoh, Hiroyuki Saito, Mikihiko Naito

    Molecular Pharmacology 91 (3) 159-166 2017年3月

    DOI: 10.1124/mol.116.105569  

    ISSN:0026-895X

    eISSN:1521-0111

    詳細を見る 詳細を閉じる

    Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics. Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRAB-P-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.

  38. Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists 査読有り

    Okazaki S, Shioi R, Noguchi-Yachide T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T

    Bioorganic and Medicinal Chemistry 24 (21) 5455-5461 2016年11月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2016.08.067  

    ISSN:0968-0896

    eISSN:1464-3391

  39. Discovery of N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel acetyl-CoA carboxylase 2 (ACC2) inhibitors with peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonistic activity 査読有り

    Okazaki S, Noguchi-Yachide T, Sakai T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T

    Bioorganic and Medicinal Chemistry 24 (21) 5258-5269 2016年11月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2016.08.045  

    ISSN:0968-0896

    eISSN:1464-3391

  40. Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists 査読有り

    Nomura S, Endo-Umeda K, Makishima M, Hashimoto Y, Ishikawa M

    ChemMedChem 11 (20) 2347-2360 2016年10月

    出版者・発行元:None

    DOI: 10.1002/cmdc.201600305  

    ISSN:1860-7179

    eISSN:1860-7187

  41. Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure 査読有り

    Michiaki Hiramatsu, Yuki Ichikawa, Shusuke Tomoshige, Makoto Makishima, Atsuya Muranaka, Masanobu Uchiyama, Takao Yamaguchi, Yuichi Hashimoto, Minoru Ishikawa

    CHEMISTRY-AN ASIAN JOURNAL 11 (15) 2210-2217 2016年8月

    出版者・発行元:WILEY-V C H VERLAG GMBH

    DOI: 10.1002/asia.201600744  

    ISSN:1861-4728

    eISSN:1861-471X

    詳細を見る 詳細を閉じる

    Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (logP) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes.

  42. Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand 査読有り

    Shusuke Tomoshige, Yuichi Hashimoto, Minoru Ishikawa

    BIOORGANIC & MEDICINAL CHEMISTRY 24 (14) 3144-3148 2016年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2016.05.035  

    ISSN:0968-0896

    eISSN:1464-3391

    詳細を見る 詳細を閉じる

    We previously reported a protein knockdown system for HaloTag-fused proteins using hybrid small molecules consisting of alkyl chloride, which binds covalently to HaloTag, linked to BE04 (2), a bestatin (3) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules was not potent. Therefore, we set out to improve this system. We report here the design, synthesis and biological evaluation of novel hybrid compounds 4a and 4b consisting of alkyl chloride linked to IAP antagonist MV1 (5). Compounds 4a and 4b were confirmed to reduce the levels of HaloTag-fused tumor necrosis factor alpha (HaloTag-TNF alpha), HaloTag-fused cell division control protein 42 (HaloTag-Cdc42), and unfused HaloTag protein in living cells more potently than did BE04-linked compound 1b. Analysis of the mode of action revealed that the reduction of HaloTag-TNF alpha is proteasome-dependent, and is also dependent on the linker structure between MV1 (5) and alkyl chloride. These compounds appear to induce ubiquitination at the HaloTag moiety of HaloTag-fused proteins. Our results indicate that these newly synthesized MV1-type hybrid compounds, 4a and 4b, are efficient tools for protein knockdown for HaloTag-fused proteins. (C) 2016 Elsevier Ltd. All rights reserved.

  43. Improving the Water-Solubility of Compounds By Molecular Modification to Disrupt Crystal Packing 査読有り

    Minoru Ishikawa, Yuichi Hashimoto

    The Practice of Medicinal Chemistry: Fourth Edition 747-765 2015年8月28日

    出版者・発行元:Elsevier Inc.

    DOI: 10.1016/B978-0-12-417205-0.00031-6  

    詳細を見る 詳細を閉じる

    Sufficient aqueous solubility is a key requirement for clinical drugs, and improvement of the aqueous solubility of drug candidates is often a major issue for medicinal chemists. The strategy of introducing hydrophilic group(s) into molecules is generally used for this purpose but is not universally effective. This chapter deals with an alternative strategy for molecular modification to improve solubility by focusing on weakening intermolecular interactions in the solid state. Relevant modifications include disruption of intermolecular hydrogen bonds, disruption of molecular planarity (increase in ratio of sp&lt sup&gt 3&lt /sup&gt -hybridized carbons, twisting of molecules, and introduction of substituents at benzylic positions), and bending molecules. Such molecular modifications have the effect of decreasing the efficiency of crystal packing, which in turn results in an increase of aqueous solubility. Improvement of aqueous solubility by as much as 350-fold was achieved in one case.

  44. Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators 査読有り

    Sayaka Nomura, Kaori Endo-Urneda, Atsushi Aoyama, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

    ACS MEDICINAL CHEMISTRY LETTERS 6 (8) 902-907 2015年8月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/acsmedchemlett.5b00170  

    ISSN:1948-5875

    詳細を見る 詳細を閉じる

    Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalirnide analogues and evaluated their structure activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and transrepressional activity. Among the compounds examined, 171 showed potent LXR-transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 171, was confirmed to have LXR-dependent transrepressional activity and to bind directly to LXR beta. Compound 171 should be useful not only as a chemical tool for studying the biological functions of LXRs transrepression but also as a candidate for a safer agent to treat inflammatory diseases.

  45. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists 査読有り

    Daisuke Kajita, Masaharu Nakamura, Yotaro Matsumoto, Minoru Ishikawa, Yuichi Hashimoto, Shinya Fujii

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 25 (16) 3350-3354 2015年8月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2015.05.045  

    ISSN:0960-894X

    eISSN:1464-3405

    詳細を見る 詳細を閉じる

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPAR alpha agonist, and evaluated their PPAR alpha/delta/gamma agonistic activity. We found that diethylsilyl derivative 20 exhibited PPAR alpha/delta agonistic activity, and we also obtained a PPAR delta-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. (C) 2015 Elsevier Ltd. All rights reserved.

  46. Structure-activity relationships of benzhydrol derivatives based on 1′-acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-κB pathway 査読有り

    Misawa T, Dodo K, Ishikawa M, Hashimoto Y, Sagawa M, Kizaki M, Aoyama H

    Bioorganic and Medicinal Chemistry 23 (9) 2241-2246 2015年5月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2015.02.039  

    ISSN:0968-0896

    eISSN:1464-3391

  47. Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton 査読有り

    Taki Sakai, Yotaro Matsumoto, Minoru Ishikawa, Kazuyuki Sugita, Yuichi Hashimoto, Nobuhiko Wakai, Akio Kitao, Era Morishita, Chikashi Toyoshima, Tomoatsu Hayashi, Tetsu Akiyama

    BIOORGANIC & MEDICINAL CHEMISTRY 23 (2) 328-339 2015年1月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2014.11.027  

    ISSN:0968-0896

    eISSN:1464-3391

    詳細を見る 詳細を閉じる

    Human sirtuin 2 (SIRT2) is an attractive target molecule for development of drugs to treat neurodegenerative diseases and cancer, because SIRT2 inhibitors have a protective effect against neurodegeneration and an anti-proliferative effect on cancer stem cells. We designed and synthesized a series of benzamide derivatives as SIRT2 inhibitor candidates. Among them, compound 17k showed the most potent SIRT2-inhibitory activity (IC50 = 0.60 mu M), with more than 150-fold selectivity over SIRT1 and SIRT3 isoforms (IC50 &gt; 100 mu M). (C) 2014 Elsevier Ltd. All rights reserved.

  48. Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules 査読有り

    Shusuke Tomoshige, Mikihiko Naito, Yuichi Hashimoto, Minoru Ishikawa

    ORGANIC & BIOMOLECULAR CHEMISTRY 13 (38) 9746-9750 2015年

    出版者・発行元:ROYAL SOC CHEMISTRY

    DOI: 10.1039/c5ob01395j  

    ISSN:1477-0520

    eISSN:1477-0539

    詳細を見る 詳細を閉じる

    We have developed a protein knockdown technology using hybrid small molecules designed as conjugates of a ligand for the target protein and a ligand for ubiquitin ligase cellular inhibitor of apoptosis protein 1 (cIAP1). However, this technology has several limitations. Here, we report the development of a novel protein knockdown system to address these limitations. In this system, target proteins are fused with HaloTag to provide a common binding site for a degradation inducer. We designed and synthesized small molecules consisting of alkyl chloride as the HaloTag-binding degradation inducer, which binds to HaloTag, linked to BE04 (2), which binds to cIAP1. Using this system, we successfully knocked down HaloTag-fused cAMP responsive element binding protein 1 (HaloTag-CREB1) and HaloTag-fused c-jun (HaloTag-c-jun), which are ligand-unknown nuclear proteins, in living cells. HaloTag-binding degradation inducers can be synthesized easily, and are expected to be useful as biological tools for pan-degradation of HaloTag-fused proteins.

  49. Structure-activity relationship-guided development of retinoic acid receptor-related orphan receptor gamma (RORγ)-selective inverse agonists with a phenanthridin-6(5H)-one skeleton from a liver X receptor ligand 査読有り

    Nishiyama Y, Nakamura M, Misawa T, Nakagomi M, Makishima M, Ishikawa M, Hashimoto Y

    Bioorganic and Medicinal Chemistry 22 (9) 2799-2808 2014年5月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2014.03.007  

    ISSN:0968-0896

    eISSN:1464-3391

  50. 7-Dehydrocholesterol metabolites produced by sterol 27-hydroxylase (CYP27A1) modulate liver X receptor activity 査読有り

    Kaori Endo-Umeda, Kaori Yasuda, Kazuyuki Sugita, Akira Honda, Miho Ohta, Minoru Ishikawa, Yuichi Hashimoto, Toshiyuki Sakaki, Makoto Makishima

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 140 7-16 2014年3月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.jsbmb.2013.11.010  

    ISSN:0960-0760

    詳細を見る 詳細を閉じる

    7-Dehydrocholesterol (7-DHC) is a common precursor of vitamin D-3 and cholesterol. Although various oxysterols, oxygenated cholesterol derivatives, have been implicated in cellular signaling pathways, 7-DHC metabolism and potential functions of its metabolites remain poorly understood. We examined 7-DHC metabolism by various P450 enzymes and detected three metabolites produced by sterol 27-hydroxylase (CYP27A1) using high-performance liquid chromatography. Two were further identified as 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC. These 7-DHC metabolites were detected in serum of a patient with Smith-Lemli-Opitz syndrome. Luciferase reporter assays showed that 25-hydroxy-7-DHC activates liver X receptor (LXR) alpha, LXR beta and vitamin D receptor and that 26/27-hydroxy-7-DHC induces activation of LXR alpha and LXR beta, although the activities of both compounds on LXRs were weak. In a mammalian two-hybrid assay, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC induced interaction between LXRa and a coactivator fragment less efficiently than a natural LXR agonist, 22(R)-hydroxycholesterol. These 7-DHC metabolites did not oppose agonist-induced LXR activation and interacted directly to LXR alpha in a manner distinct from a potent agonist. These findings indicate that the 7-DHC metabolites are partial LXR activators. Interestingly, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC suppressed mRNA expression of sterol regulatory element-binding protein 1c, an LXR target gene, in HepG2 cells and HaCaT cells, while they weakly increased mRNA levels of ATP-binding cassette transporter A1, another LXR target, in HaCaT cells. Thus, 7-DHC is catabolized by CYP27A1 to metabolites that act as selective LXR modulators. (C) 2013 Elsevier Ltd. All rights reserved.

  51. Structure-activity relationships of bisphenol a analogs at estrogen receptors (ERs): Discovery of an ERα-selective antagonist 査読有り

    Maruyama K, Nakamura M, Tomoshige S, Sugita K, Makishima M, Hashimoto Y, Ishikawa M

    Bioorganic and Medicinal Chemistry Letters 23 (14) 4031-4036 2013年7月15日

    DOI: 10.1016/j.bmcl.2013.05.067  

    ISSN:0960-894X 1464-3405

  52. 分子構造の非平面化&middot;非対称化による溶解度向上策と創薬化学への応用 査読有り

    石川稔, 橋本祐一

    有機合成化学協会誌 71 (6) 625-636 2013年6月

    出版者・発行元:None

    DOI: 10.5059/yukigoseikyokaishi.71.625  

    ISSN:0037-9980

    eISSN:1883-6526

  53. Structure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with coactivators 査読有り

    Yusuke Mita, Kosuke Dodo, Tomomi Noguchi-Yachide, Yuichi Hashimoto, Minoru Ishikawa

    BIOORGANIC & MEDICINAL CHEMISTRY 21 (4) 993-1005 2013年2月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2012.11.042  

    ISSN:0968-0896

    詳細を見る 詳細を閉じる

    Suppression of vitamin D receptor (VDR)-mediated transcription is expected to be of therapeutic value in Paget's disease of bone. It is known that interaction between VDR and coactivators is necessary for VDR transactivation, and the interaction occurs when VDR recognizes an LXXLL peptide motif of coactivators. We previously reported that benzodiazepine derivatives designed as LXXLL. peptide mimetics inhibited the interaction of VDR and coactivators, and reduced VDR transcription. Here, we investigated the structure-activity relationship of 7- and 8-substituted benzodiazepine derivatives, and established that the amino group at the 8-position is critical for the inhibitory activity. (C) 2012 Elsevier Ltd. All rights reserved.

  54. Small-molecular, non-peptide, non-ATP-competitive polo-like kinase 1 (Plk1) inhibitors with a terphenyl skeleton 査読有り

    Yusuke Mita, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto

    Bioorganic and Medicinal Chemistry 21 (3) 608-617 2013年2月1日

    DOI: 10.1016/j.bmc.2012.11.054  

    ISSN:0968-0896 1464-3391

    詳細を見る 詳細を閉じる

    Polo-like kinase (Plk) 1 is a serine-threonine protein kinase that plays a role in cell division, and its overexpression is highly correlated with aggressiveness and prognosis of many cancers. We have designed, synthesized and evaluated a series of terphenyl compounds as inhibitors of the kinase activity of Plk1. Some of them act as non-ATP-competitive Plk1 inhibitors. © 2012 Elsevier Ltd. All rights reserved.

  55. Design, Synthesis, and Biological Evaluation of Novel Transrepression-Selective Liver X Receptor (LXR) Ligands with 5,11-Dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one Skeleton 査読有り

    Atsushi Aoyama, Kaori Endo-Umeda, Kenji Kishida, Kenji Ohgane, Tomomi Noguchi-Yachide, Hiroshi Aoyama, Minoru Ishikawa, Hiroyuki Miyachi, Makoto Makishima, Yuichi Hashimoto

    JOURNAL OF MEDICINAL CHEMISTRY 55 (17) 7360-7377 2012年9月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/jm3002394  

    ISSN:0022-2623

    eISSN:1520-4804

    詳細を見る 詳細を閉じる

    To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 mu M but showed no transactivational activity even at 30 mu M. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXR alpha. Next, further structural modification was performed with the guidance of docking simulations with LXR alpha, focusing on enhancing the binding of the ligands with LXR alpha through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.

  56. Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist 査読有り

    Yukihiro Itoh, Minoru Ishikawa, Risa Kitaguchi, Keiichiro Okuhira, Mikihiko Naito, Yuichi Hashimoto

    Bioorganic and Medicinal Chemistry Letters 22 (13) 4453-4457 2012年7月1日

    DOI: 10.1016/j.bmcl.2012.04.134  

    ISSN:0960-894X

    eISSN:1464-3405

    詳細を見る 詳細を閉じる

    Protein knockdown can be achieved by the use of a small molecule that possesses affinity for both the target protein and ubiquitin ligase. We have designed such a degradation-inducing molecule targeting cIAP1 and CRABP-II, which are involved in proliferation of several cancer cell lines and in neuroblastoma growth, respectively. As a CRABP-II-recognizing moiety, all-trans retinoic acid (ATRA, 3), a physiological ligand of CRABP, was chosen. As a cIAP1-recognizing moiety, MV1 (5), which is a cIAP1/cIAP2/XIAP pan-ligand, was chosen. Although cIAP1 itself possesses ubiquitin ligase activity, we expected that its decomposition would be efficiently mediated by related molecules, including cIAP2 and XIAP, which also possess ubiquitin ligase activity. The designed degradation inducer 6, in which ATRA (3) and MV1 (5) moieties are connected via a linker, was synthesized and confirmed to induce efficient degradation of both cIAP1 and CRABP-II. It showed potently inhibited the proliferation of IMR32 cells. © 2012 Elsevier Ltd. All rights reserved.

  57. Design, synthesis and biological evaluation of nuclear receptor-degradation inducers 査読有り

    Yukihiro Itoh, Risa Kitaguchi, Minoru Ishikawa, Mikihiko Naito, Yuichi Hashimoto

    Bioorganic and Medicinal Chemistry 19 (22) 6768-6778 2011年11月15日

    DOI: 10.1016/j.bmc.2011.09.041  

    ISSN:0968-0896

    eISSN:1464-3391

    詳細を見る 詳細を閉じる

    Compounds that regulate the function(s) of nuclear receptors (NRs) are useful for biological studies and as candidate therapeutic agents. Most such compounds are agonists or antagonists. On the other hand, we have developed specific protein degradation inducers, which we designated as SNIPERs (Specific and Nongenetic IAPs-dependent Protein ERasers), for selective degradation of target proteins. SNIPERs are hybrid molecules consisting of an appropriate ligand for the protein of interest, coupled to a ligand for inhibitor of apoptosis proteins (IAPs), which target the bound protein for polyubiquitination and proteasomal degradation. We considered that protein knockdown with SNIPERs would be a promising alternative approach for modulating NR function. In this study, we designed and synthesized degradation inducers targeting retinoic acid receptor (RAR), estrogen receptor (ER), and androgen receptor (AR). These newly synthesized RAR, ER, and AR SNIPERs, 9, 11, and 13, respectively, were confirmed to significantly reduce the levels of the corresponding NRs in live cells. © 2011 Elsevier Ltd. All rights reserved.

  58. Confirmation of molecular planarity disruption effect on aqueous solubility improvement of β-naphthoflavone analogs 査読有り

    Fujita Y, Yonehara M, Kitahara K, Shimokawa J, Hashimoto Y, Ishikawa M

    Heterocycles 83 (11) 2563-2575 2011年11月

    出版者・発行元:None

    DOI: 10.3987/COM-11-12352  

    ISSN:0385-5414

  59. Inhibition of Restriction Enzymes EcoRI, BamHI and HindIII by Phenethylphenylphthalimides Derived from Thalidomide 査読有り

    Kazunori Motoshima, Minoru Ishikawa, Yuichi Hashimoto, Kazuyuki Sugita

    CHEMICAL & PHARMACEUTICAL BULLETIN 59 (7) 880-884 2011年7月

    出版者・発行元:PHARMACEUTICAL SOC JAPAN

    DOI: 10.1248/cpb.59.880  

    ISSN:0009-2363

    詳細を見る 詳細を閉じる

    We discovered inhibitors of the restriction enzymes EcoRI, BamHI and HindIII by screening our library of compounds with a phenethylphenylphthalimide skeleton, based on alpha-glucosidase inhibitors and liver X receptor antagonists derived from thalidomide. Structural development afforded the potent restriction enzyme inhibitors 25 and 26.

  60. Development of target protein-selective degradation inducer for protein knockdown 査読有り

    Yukihiro Itoh, Minoru Ishikawa, Risa Kitaguchi, Shinichi Sato, Mikihiko Naito, Yuichi Hashimoto

    Bioorganic and Medicinal Chemistry 19 (10) 3229-3241 2011年5月15日

    DOI: 10.1016/j.bmc.2011.03.057  

    ISSN:0968-0896

    eISSN:1464-3391

    詳細を見る 詳細を閉じる

    Our previous technique for inducing selective degradation of target proteins with ester-type SNIPER (Specific and Nongenetic Inhibitor-of-apoptosis- proteins (IAPs)-dependent Protein ERaser) degrades both the target proteins and IAPs. Here, we designed a small-molecular amide-type SNIPER to overcome this issue. As proof of concept, we synthesized and biologically evaluated an amide-type SNIPER which induces selective degradation of cellular retinoic acid binding protein II (CRABP-II), but not IAPs. Such small-molecular, amide-type SNIPERs that induce target protein-selective degradation without affecting IAPs should be effective tools to study the biological roles of target proteins in living cells. © 2011 Elsevier Ltd. All rights reserved.

  61. Peroxisome proliferator-activated receptor agonists with phenethylphenylphthalimide skeleton derived from thalidomide-related liver X receptor antagonists: Relationship between absolute configuration and subtype selectivity 査読有り

    Kazunori Motoshima, Minoru Ishikawa, Yuichi Hashimoto, Kazuyuki Sugita

    BIOORGANIC & MEDICINAL CHEMISTRY 19 (10) 3156-3172 2011年5月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2011.03.065  

    ISSN:0968-0896

    詳細を見る 詳細を閉じる

    Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure-activity relationship analysis and docking studies led us to the potent PPAR agonists 13c-e. The absolute configuration of 13c-e affects the PPAR subtype selectivity. (C) 2011 Elsevier Ltd. All rights reserved.

  62. Non-competitive and selective dipeptidyl peptidase IV inhibitors with phenethylphenylphthalimide skeleton derived from thalidomide-related α-glucosidase inhibitors and liver X receptor antagonists 査読有り

    Motoshima K, Sugita K, Hashimoto Y, Ishikawa M

    Bioorganic and Medicinal Chemistry Letters 21 (10) 3041-3045 2011年5月

    出版者・発行元:None

    DOI: 10.1016/j.bmcl.2011.03.026  

    ISSN:0960-894X

  63. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein 査読有り

    Keiichiro Okuhira, Nobumichi Ohoka, Kimie Sai, Tomoko Nishimaki-Mogami, Yukihiro Itoh, Minoru Ishikawa, Yuichi Hashimoto, Mikihiko Naito

    FEBS Letters 585 (8) 1147-1152 2011年4月

    DOI: 10.1016/j.febslet.2011.03.019  

    ISSN:0014-5793

    詳細を見る 詳細を閉じる

    Manipulation of protein stability with small molecules is a challenge in the field of drug discovery. Here we show that cellular retinoic acid binding protein-II (CRABP-II) can be specifically degraded by a novel compound, SNIPER-4, consisting of (-)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l- leucine methyl ester and all-trans retinoic acid that are ligands for cellular inhibitor of apoptosis protein 1 (cIAP1) and CRABP-II, respectively. Mechanistic analysis revealed that SNIPER-4 induces cIAP1-mediated ubiquitylation of CRABP-II, resulting in the proteasomal degradation. The protein knockdown strategy employing the structure of SNIPER-4 could be applicable to other target proteins. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  64. FURTHER APPLICATION OF THE MULTI-TEMPLATE APPROACH FOR CREATION OF BIOLOGICAL RESPONSE MODIFIERS: DISCOVERY OF A NEW CLASS OF MULTIFUNCTIONAL ANTI-DIABETIC AGENTS 査読有り

    Kazunori Motoshima, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto, Kazuyuki Sugita

    HETEROCYCLES 82 (2) 1083-+ 2011年3月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.3987/REV-10-SR(E)7  

    ISSN:0385-5414

    詳細を見る 詳細を閉じる

    We have previously employed the multi-template approach to create many types of biologically active compounds. In this review, we focus on extension of the multi-template approach to develop candidate anti-diabetic and anti-metabolic syndrome agents with a well-balanced range of activities.

  65. Improvement in Aqueous Solubility in Small Molecule Drug Discovery Programs by Disruption of Molecular Planarity and Symmetry 査読有り

    Minoru Ishikawa, Yuichi Hashimoto

    JOURNAL OF MEDICINAL CHEMISTRY 54 (6) 1539-1554 2011年3月

    出版者・発行元:AMER CHEMICAL SOC

    DOI: 10.1021/jm101356p  

    ISSN:0022-2623

  66. Novel selective anti-androgens with a diphenylpentane skeleton 査読有り

    Keisuke Maruyama, Tomomi Noguchi-Yachide, Kazuyuki Sugita, Yuichi Hashimoto, Minoru Ishikawa

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 20 (22) 6661-6666 2010年11月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2010.09.011  

    ISSN:0960-894X

    詳細を見る 詳細を閉じる

    We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC(50): 0.13 mu M) than clinically used anti-androgen bicalutamide (IC(50): 0.67 mu M) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds. (C) 2010 Elsevier Ltd. All rights reserved.

  67. Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator-activated receptor (PPAR) δ-selective partial agonists by disruption of molecular planarity/symmetry 査読有り

    Kasuga J.-I, Ishikawa M, Yonehara M, Makishima M, Hashimoto Y, Miyachi H

    Bioorganic and Medicinal Chemistry 18 (20) 7164-7173 2010年10月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2010.08.041  

    ISSN:0968-0896

  68. Development of tryptase inhibitors derived from thalidomide 査読有り

    Masashi Tetsuhashi, Minoru Ishikawa, Mariko Hashimoto, Yuichi Hashimoto, Hiroshi Aoyama

    BIOORGANIC & MEDICINAL CHEMISTRY 18 (14) 5323-5338 2010年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2010.05.037  

    ISSN:0968-0896

    詳細を見る 詳細を閉じる

    A novel series of tryptase inhibitors with a N-phenylphthalimide skeleton structurally derived from thalidomide (1) has been developed. Structure-activity relationship studies led to a potent and selective tryptase inhibitor, 2-(4-cyanophenyl) isoindole-1,3-dione-5-yl 3-(2-aminopyridin-5-yl) propanoate (7), with the IC(50) value of 78 nM. (C) 2010 Elsevier Ltd. All rights reserved.

  69. Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide 査読有り

    Yuma Iwai, Hitoshi Takahashi, Dai Hatakeyama, Kazunori Motoshima, Minoru Ishikawa, Kazuyuki Sugita, Yuichi Hashimoto, Yuichi Harada, Shigeyuki Itamura, Takato Odagiri, Masato Tashiro, Yoshihisa Sei, Kentaro Yamaguchi, Takashi Kuzuhara

    BIOORGANIC & MEDICINAL CHEMISTRY 18 (14) 5379-5390 2010年7月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmc.2010.05.035  

    ISSN:0968-0896

    eISSN:1464-3391

    詳細を見る 詳細を閉じる

    Swine-origin influenza A virus has caused pandemics throughout the world and influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable. Influenza A expresses an RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from thalidomide (PPT analogs). For this screen we used a PA endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA endonuclease activity and retard the growth of influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA endonuclease assay in the screening of anti-influenza drugs and are therefore useful for future strategies to develop novel anti-influenza A drugs and for mapping the function of the influenza A RNA polymerase subunits. (C) 2010 Elsevier Ltd. All rights reserved.

  70. Protein knockdown using methyl bestatin-ligand hybrid molecules: Design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins 査読有り

    Yukihiro Itoh, Minoru Ishikawa, Mikihiko Naito, Yuichi Hashimoto

    Journal of the American Chemical Society 132 (16) 5820-5826 2010年4月

    DOI: 10.1021/ja100691p  

    ISSN:0002-7863

    eISSN:1520-5126

    詳細を見る 詳細を閉じる

    Induction of selective degradation of target proteins by small molecules (protein knockdown) would be useful for biological research and treatment of various diseases. To achieve protein knockdown, we utilized the ubiquitin ligase activity of cellular inhibitor of apoptosis protein 1 (cIAP1), which is activated by methyl bestatin (MeBS, 2). We speculated that formation of an artificial (nonphysiological) complex of cIAP1 and a target protein would be induced by a hybrid molecule consisting of MeBS (2) linked to a ligand of the target protein, and this would lead to cIAP1-mediated ubiquitination and subsequent proteasomal degradation of the target protein. To verify this hypothesis, we focused on cellular retinoic acid-binding proteins (CRABP-I and -II) and designed hybrid molecules (compounds 4) consisting of MeBS (2) coupled via spacers of various lengths to all-trans retinoic acid (ATRA, 3), a ligand of CRABPs. Compounds 4 induced selective loss of CRABP-I and -II proteins in cells. We confirmed that 4b induced formation of a complex of cIAP1 and CRABP-II in vitro and induced proteasomal degradation of CRABP-II in cells. When neuroblastoma IMR-32 cells were treated with 4b, the level of CRABP-II was reduced and cell migration was inhibited, suggesting potential value of CRABP-II-targeting therapy for controlling tumor metastasis. Our results indicate that 4b possesses sufficient activity, permeability, and stability in cells to be employed in cellular assays. Hybrid molecules such as 4 should be useful not only as chemical tools for studying the biological/physiological functions of CRABPs but also as candidate therapeutic agents targeting CRABPs. © 2010 American Chemical Society.

  71. LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators 査読有り

    Yusuke Mita, Kosuke Dodo, Tomomi Noguchi-Yachide, Hiroyuki Miyachi, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 20 (5) 1712-1717 2010年3月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2010.01.079  

    ISSN:0960-894X

    詳細を見る 詳細を閉じる

    Suppression of vitamin D receptor (VDR)-mediated transcription is expected be of therapeutic value in Paget&apos;s disease. Once an agonist activates VDR, recruitment of additional coactivator proteins is essential for transcription. Neither non-secosteroidal VDR antagonists nor non-peptide coactivator binding inhibitors for VDR have been reported so far. Based on the X-ray structure of VDR and an LXXLL-containing peptide fragment of the coactivator (where L is leucine and X is any amino acid), which adopts a partially alpha-helical conformation, benzodiazepine molecules were rationally designed as non-peptide coactivator mimetics. TR-FRET assay showed that the synthesized compounds inhibited the interaction between VDR and a coactivator peptide fragment. Compound 2 showed an IC(50) of 20 mu M. Compound 2 also inhibited VDR-mediated transcription, and this activity was independent of the concentration of co-existing agonist. Furthermore, compound 2 did not inhibit estrogen receptor alpha-mediated transcription, indicating that it is not a non-selective inhibitor of other nuclear receptors. (C) 2010 Elsevier Ltd. All rights reserved.

  72. β-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists: Improvement of solubility by disruption of molecular planarity 査読有り

    Fujita Y, Yonehara M, Tetsuhashi M, Noguchi-Yachide T, Hashimoto Y, Ishikawa M

    Bioorganic and Medicinal Chemistry 18 (3) 1194-1203 2010年2月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2009.12.036  

    ISSN:0968-0896

  73. Glycogen phosphorylase a inhibitors with a phenethylphenylphthalimide skeleton derived from thalidomide-related α-glucosidase inhibitors and liver X receptor antagonists 査読有り

    Motoshima K, Ishikawa M, Sugita K, Hashimoto Y

    Biological and Pharmaceutical Bulletin 32 (9) 1618-1620 2009年9月

    出版者・発行元:None

    DOI: 10.1248/bpb.32.1618  

    ISSN:0918-6158

  74. Separation of α-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXRα-selective antagonists 査読有り

    Motoshima K, Noguchi-Yachide T, Sugita K, Hashimoto Y, Ishikawa M

    Bioorganic and Medicinal Chemistry 17 (14) 5001-5014 2009年7月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2009.05.066  

    ISSN:0968-0896

  75. Pseurotin A and its analogues as inhibitors of immunoglobuline E production 査読有り

    Minoru Ishikawa, Tomohisa Ninomiya, Hirotomo Akabane, Nobuaki Kushida, Go Tsujiuchi, Makoto Ohyama, Shuichi Gomi, Keiko Shito, Takashi Murata

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 19 (5) 1457-1460 2009年3月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.bmcl.2009.01.029  

    ISSN:0960-894X

    詳細を見る 詳細を閉じる

    A natural product, pseurotin A inhibits IgE production in vitro. Wide variety of chemical modi. cation of pseurotin A was performed. Structure-activity relationship studies of pseurotin analogues elucidated that 10-deoxypseurotin A strongly inhibits IgE production with IC(50) of 0.066 mu M. An immunosuppressive activity of another natural product, synerazol was also found. (C) 2009 Elsevier Ltd. All rights reserved.

  76. Synthesis of potent α<inf>v</inf>β<inf>3</inf>/α <inf>IIb</inf>β<inf>3</inf> dual antagonists tricyclic pharmacophore-based molecules and their selectivity control 査読有り

    Ishikawa M, Kubota D, Ajito K

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 66 (11) 1093-1104 2008年11月

    出版者・発行元:None

    ISSN:0037-9980

  77. Chemical Modification of Pseurotin A: One-pot Synthesis of Synerazol and Pseurotin E and Determination of Absolute Stereochemistry of Pseurotin E 査読有り

    Minoru Ishikawa, Tomohisa Ninomiya

    JOURNAL OF ANTIBIOTICS 61 (11) 692-695 2008年11月

    出版者・発行元:JAPAN ANTIBIOTICS RESEARCH ASSOC

    DOI: 10.1038/ja.2008.99  

    ISSN:0021-8820

    詳細を見る 詳細を閉じる

    Two natural products, synerazol and pseurotin E, were synthesized from the natural product pseurotin A in 58% and 57% yields, respectively in one-pot procedures. This work also establishes the absolute stereochemistry of pseurotin E.

  78. A scalable synthesis of MN-447, an antagonist for integrins α<inf>v</inf>β<inf>3</inf> and α<inf>IIb</inf>β <inf>3</inf> 査読有り

    Ishikawa M, Tsushima M, Kubota D, Yanagisawa Y, Hiraiwa Y, Kojima Y, Ajito K, Anzai N

    Organic Process Research and Development 12 (4) 596-602 2008年7月

    出版者・発行元:None

    DOI: 10.1021/op800073z  

    ISSN:1083-6160

  79. Enantioselective total synthesis of (+)-sarcodictyenone 査読有り

    Takako Yamazaki, Minoru Ishikawa, Miki Uemura, Yuko Kanda, Hisashi Takei, Morio Asaoka

    TETRAHEDRON 64 (8) 1895-1900 2008年2月

    出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD

    DOI: 10.1016/j.tet.2007.11.088  

    ISSN:0040-4020

    詳細を見る 詳細を閉じる

    The first enantioselective total synthesis of (+)-sarcodictyenone is described [4.3% overall yield from (5R,6R)-6-methyl-5-trimethylsily-2-cyclohexenone]. This work establishes the absolute stereochemistry of the natural product. (C) 2007 Elsevier Ltd. All rights reserved.

  80. Tricyclic pharmacophore-based molecules as novel integrin α<inf>v</inf>β<inf>3</inf>antagonists. Part IV: Preliminary control of α<inf>v</inf>β<inf>3</inf>selectivity by meta-oriented substitution 査読有り

    Kubota D, Ishikawa M, Ishikawa M, Yahata N, Murakami S, Fujishima K, Kitakaze M, Ajito K

    Bioorganic and Medicinal Chemistry 14 (12) 4158-4181 2006年6月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2006.01.062  

    ISSN:0968-0896

  81. Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/α IIbβ3 dual activity and improved water solubility 査読有り

    Ishikawa M, Hiraiwa Y, Kubota D, Tsushima M, Watanabe T, Murakami S, Ouchi S, Ajito K

    Bioorganic and Medicinal Chemistry 14 (7) 2131-2150 2006年4月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2005.10.055  

    ISSN:0968-0896

  82. Tricyclic pharmacophore-based molecules as novel integrin α<inf>v</inf>β<inf>3</inf>antagonists. Part 2: Synthesis of potent α<inf>v</inf>β<inf>3</inf>/α<inf>IIb</inf>β<inf>3</inf>dual antagonists 査読有り

    Ishikawa M, Kubota D, Yamamoto M, Kuroda C, Iguchi M, Koyanagi A, Murakami S, Ajito K

    Bioorganic and Medicinal Chemistry 14 (7) 2109-2130 2006年4月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2005.10.061  

    ISSN:0968-0896

  83. Tricyclic pharmacophore-based molecules as novel integrin α<inf>v</inf>β<inf>3</inf>antagonists. Part 1: Design and synthesis of a lead compound exhibiting α<inf>v</inf>β<inf>3</inf>/ α<inf>IIb</inf>β<inf>3</inf>dual antagonistic activity 査読有り

    Kubota D, Ishikawa M, Yamamoto M, Murakami S, Hachisu M, Katano K, Ajito K

    Bioorganic and Medicinal Chemistry 14 (7) 2089-2108 2006年4月

    出版者・発行元:None

    DOI: 10.1016/j.bmc.2005.10.060  

    ISSN:0968-0896

︎全件表示 ︎最初の5件までを表示

MISC 9

  1. 標的タンパク質を分解する低分⼦ 〜疾患関連タンパク質をゴミ箱へ〜 招待有り 査読有り

    石川稔

    生命化学研究レター 62 (4) 9-14 2021年4月

  2. 標的タンパク質分解薬の動向ーPROTACsの先を見据えて 招待有り

    石川稔, 友重秀介

    月刊化学 75 (12) 70-71 2020年11月

  3. Excellence in Medicinal Chemistry Research from Japan 査読有り

    Shaomeng Wang、Gunda Georg、Minoru Ishikawa、Tomohiko Ohwada、Satoshi Shuto、Takayoshi Suzuki

    Journal of Medicinal Chemistry 63 (17) 8877-8879 2020年8月

  4. 高活性なリガンド創出に向けたユビキチンリガーゼcIAP1-BIR3ドメインの結晶構造解析

    岡部真琴, 佐藤伸一, 佐藤伸一, 横山武司, 友重秀介, 石川稔, 田中良和

    日本分子生物学会年会プログラム・要旨集(Web) 43rd 2020年

  5. Cover Picture: Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure (Chem. Asian J. 15/2016)

    Michiaki Hiramatsu, Yuki Ichikawa, Shusuke Tomoshige, Makoto Makishima, Atsuya Muranaka, Masanobu Uchiyama, Takao Yamaguchi, Yuichi Hashimoto, Minoru Ishikawa

    Chemistry - An Asian Journal 11 (15) 2086 2016年8月5日

    出版者・発行元:John Wiley and Sons Ltd

    DOI: 10.1002/asia.201600924  

    ISSN:1861-471X 1861-4728

  6. Liver X Receptor(LXR)リガンドの構造展開によるTransrepression作用選択的リガンドの創製

    青山惇, 梅田(遠藤)香織, 谷内出(野口)友美, 石川稔, 宮地弘幸, 槇島誠, 橋本祐一

    日本薬学会年会要旨集 132nd (2) 2012年

    ISSN:0918-9823

  7. LXXLL配列を模倣したビタミンD受容体−コアクチベーター相互作用阻害物質の創製 招待有り

    三田 裕介, 橋本 祐一, 石川 稔

    ビタミン 85 (1) 25-26 2011年

    出版者・発行元:公益社団法人 日本ビタミン学会

    DOI: 10.20632/vso.85.1_25  

    ISSN:0006-386X

  8. 2-I-18 LXXLL配列を模倣したビタミンD受容体-コアクチベーター相互作用阻害物質の創製(一般演題,日本ビタミン学会第62回大会発表要旨)

    三田 裕介, 〓〓 孝介, 谷内出 友美, 宮地 弘幸, 橋本 祐一, 石川 稔

    ビタミン 84 (4) 175-175 2010年

    出版者・発行元:公益社団法人 日本ビタミン学会

    DOI: 10.20632/vso.84.4_175_2  

    ISSN:0006-386X

  9. インテグリンαvβ3/αIIbβ3デュアル拮抗作用を有するRGDペプチド等価体の創製 招待有り

    石川 稔

    ペプチドニュースレター 77 4-6 2010年

︎全件表示 ︎最初の5件までを表示

書籍等出版物 7

  1. 創薬化学のすゝめ

    日本薬学会医薬化学部会 2023年6月

  2. 研究開発の俯瞰報告書 ライフサイエンス・臨床医学分野(2023年)

    石川稔

    国立研究開発法人科学技術振興機構 2023年4月

  3. 創薬科学・医薬化学

    橘高, 敦史

    化学同人 2022年10月

    ISBN: 9784759823325

  4. 研究開発の俯瞰報告書 ライフサイエンス・臨床医学分野(2021年)

    石川稔

    国立研究開発法人科学技術振興機構 2021年4月

  5. The Practice of Medicinal Chemistry, 4th edition

    Minoru Ishikawa, Yuichi Hashimoto

    2015年

  6. 生体有機化学

    石川 稔

    東京化学同人 2012年

  7. 創薬支援研究の展望

    石川稔, 味戸慶一

    シーエムシー出版 2008年

︎全件表示 ︎最初の5件までを表示

講演・口頭発表等 52

  1. 神経変性疾患治療を目指した有機化学的アプローチ 招待有り

    石川稔

    ニューモダリティと有機合成化学」研究部会 第10回勉強会 2023年11月27日

  2. タンパク質分解薬の概要 招待有り

    石川稔

    第40回メディシナルケミストリーシンポジウム つながり醸成企画ー未来を切り拓く創薬技術ー 2023年11月14日

  3. Medicinal chemistry for neurodegenerative disorders 招待有り

    Minoru Ishikawa

    Tohoku University Chemistry Summer School 2023 2023年8月9日

  4. PROTACs for neurodegenerative disorders 招待有り

    Minoru Ishikawa

    2nd Targeted Protein Degradation Conference in Japan 2023年7月26日

  5. 新創薬モダリティを指向した創薬化学研究 招待有り

    石川稔

    東京工業大学大学院ライフエンジニアリング特別講義第四- 低分子創薬の革新的モダリティーと最前線 - 2023年6月30日

  6. 神経変性疾患治療に対する創薬手法 招待有り

    石川稔

    日本薬学会東海支部特別講演会 2023年6月13日

  7. 神経変性疾患治療を目指した有機化学的アプローチ 招待有り

    石川稔

    有機合成化学協会東北支部_仙台地区春の講演会 2023年5月20日

  8. Novel drug discovery for neurodegenerative disorders 招待有り

    Minoru Ishikawa

    日本薬学会第143年会 Frontiers in Synthetic Medicinal Chemistry 2023 2023年3月27日

  9. 標的タンパク質を分解する低分子PROTACの創製 招待有り

    石川稔

    日本農芸化学会2023年度広島大会シンポジウム ケモテクノロジーが拓くユビキチン研究の新潮流 2023年3月15日

  10. Medicinal chemistry for neurodegenerative disorders 招待有り

    Minoru Ishikawa

    8th Seoul National University Symposium on Medicinal Chemistry 2023年1月13日

  11. PROTACs for neurodegenerative disorders 招待有り

    Minoru Ishikawa

    the international symposium "Ubiquitin New Frontier ~from Neo-Biology to Targeted Protein Degradation~" 2022年12月4日

  12. タンパク質分解薬の創製研究 招待有り

    石川稔

    第54回若手ペプチド夏の勉強会 2022年8月8日

  13. タンパク質分解の創薬 招待有り

    石川稔

    東京薬科大学 生命科学部 公開講義 2022年7月5日

  14. 細胞内の標的タンパク質を分解誘導する低分子 招待有り

    石川稔

    第74回日本細胞生物学会大会 シンポジウム[新学術] ユビキチン研究のニューフロンティア 2022年6月28日

  15. 標的タンパク質を分解誘導する低分子 招待有り

    石川稔

    日本ケミカルバイオロジー学会第16回年会 新学術領域研究「ケモテクノロジーが拓くユビキチンニューフロンティア」共催ミニシンポジウム 2022年6月1日

  16. 疾患関連タンパク質を分解誘導する低分子 招待有り

    石川稔

    令和3年度第四回東名産学官・医連携研究会 2022年2月1日

  17. Chemical biology of bioactive molecules 招待有り

    石川稔

    International Symposium for Interface Oral Health Science 2022 2022年1月15日

  18. 凝集性タンパク質を分解するストラテジー 招待有り

    石川稔

    第40回日本認知症学会学術集会 オンラインシンポジウム新しいケミカルバイオロジー手法の開発と神経変性疾患への展開 2021年11月

  19. 神経変性疾患の原因タンパク質分解薬の創製 招待有り

    石川稔

    CBI学会 第424回研究講演会「プロテインノックダウン法による創薬パラダイムシフト」 2021年6月25日

  20. 細胞内で標的タンパク質を減少させる機能性分子 招待有り

    石川稔

    日本薬学会第141回年会シンポジウム 薬学における生命指向型化学(機能性分子を基軸とした生命現象の可視化・解明) 2021年3月29日

  21. 分子間相互作用低下による生物活性物質の水溶性向上策 招待有り

    石川稔

    日本薬学会第141回年会シンポジウム 薬学領域に貢献するメディシナルケミストリー最前線 2021年3月27日

  22. 標的タンパク質を分解誘導するケミカルバイオロジー手法 招待有り

    石川稔

    第93回日本生化学会大会 シンポジウム「化学で攻める新しい創薬のカタチ」 2020年9月15日

  23. 細胞内の標的タンパク質を減少させる低分子 招待有り

    石川稔

    日本薬学会第140年会 シンポジウム 薬学における生命指向型化学(革新的ケミカルツールを用いた生命科学研究の最前線) 2020年3月26日

  24. 疾患関連タンパク質のケミカルノックダウンと神経変性疾患への展開 招待有り

    石川 稔

    大正製薬株式会社講演会 2020年2月7日

  25. 細胞内の疾患関連タンパク質を減少させる有機化学的手法 招待有り

    石川 稔

    2019年度 後期(秋季)有機合成化学講習会 有機合成化学が切り拓く新しい世界-独創的アプローチの最前線- 2019年11月21日

  26. ワルなタンパク質をぶっ壊す小柄な薬 招待有り

    石川 稔

    第9回CSJ化学フェスタ2019 文科省科研費新学術領域研究「ケモテクノロジーが拓くユビキチンニューフロンティア」特別企画 ユビキチンは令和の新創薬ターゲット 2019年10月16日

  27. 細胞内の標的タンパク質の寿命を短縮する低分子 招待有り

    石川 稔

    第13回バイオ関連化学シンポジウム フォーカスドセッション「最先端合成化学を駆使したバイオ関連化学最前線」 2019年9月6日

  28. Degradation of target proteins by small molecules 招待有り

    17th Annual Congress of International Drug Discovery Science & Technology 2019年7月25日

  29. 低分子によるタンパク質ノックダウン 招待有り

    石川 稔

    日本ケミカルバイオロジー学会第14回年会 新学術領域研究「ケモユビキチン」共催ミニシンポジウム 2019年6月11日

  30. 低分子創薬の守備範囲を拡げる有機化学的戦略:標的タンパク質のケミカルノックダウンと、水溶性を向上させる分子設計 招待有り

    石川 稔

    東京理科大学理工学部生物有機化学特別セミナー 2019年5月24日

  31. 標的タンパク質のケミカルノックダウンと応用展開 招待有り

    石川 稔

    日本薬学会第139年会 シンポジウム 選択的タンパク質分解医薬品開発の最前線 2019年3月23日

  32. 低分子創薬の守備範囲を拡げる戦略:標的タンパク質のケミカルノックダウンと、水溶性を向上させる分子設計 招待有り

    石川 稔

    第23回神戸ポートアイランド創薬フォーラム 2018年12月

  33. 標的タンパク質のケミカルノックダウン 招待有り

    石川 稔

    大塚創薬化学シンポジウム2018 2018年11月

  34. Selective degradation of target proteins by small molecules 招待有り

    石川 稔

    The Third A3 Roundtable Meeting on Chemical Probe Research Hub 2018年11月

  35. 標的タンパク質のケミカルノックダウン 招待有り

    石川 稔

    理化学研究所 Pioneering Project: Chemical Probe(生命現象探索分子)第一回合同合宿セミナー 2018年10月

  36. 疾患関連タンパク質の寿命を縮める低分子 招待有り

    石川 稔

    熊本大学工学部物質生命化学科 第7回生命化学セミナー 2018年10月

  37. 薬らしい物性を指向した核内受容体リガンドの創製研究 招待有り

    石川 稔

    日本レチノイド研究会第29回学術集会 若手シンポジウム 2018年10月

  38. 低分子創薬の守備範囲を拡げる戦略:標的タンパク質のケミカルノックダウンと、水溶性を向上させる分子設計 招待有り

    石川 稔

    名古屋大学大学院創薬科学研究科 第79回創薬科学セミナー 2018年7月

  39. Selective degradation of target proteins by small molecules 招待有り

    石川 稔

    第2回A3若手研究者ミーティング 2018年7月

  40. 低分子創薬のフィールドを拡げる手法開発:タンパク質分解誘導薬と水溶性向上策 招待有り

    石川 稔

    大阪大学 新適塾「未来創薬への誘い」第42回 2018年4月

  41. ユビキチン化により標的タンパク質を分解する低分子 招待有り

    石川 稔

    第1回ユビキチン研究会 2018年1月

  42. 「匠の化合物」で生命を操れるか? 招待有り

    石川 稔

    第6回CSJ化学フェスタ2016 テーマ企画 私たちの生活に欠かせない有機合成化学!~「匠の技」で豊かな分子と社会を生み出そう!~ 2016年11月

  43. 低分子創薬のふたつの新戦略:タンパク質分解と、水溶性向上 招待有り

    石川 稔

    第1回先端ケミカルバイオロジー研究会 2016年6月

  44. タンパク質を特異的に分解する低分子の新展開 招待有り

    石川 稔

    第30回バイオテクノロジー懇談会 2016年2月

  45. 低分子によりタンパク質を特異的に減少させる「タンパク質ノックダウン法」の開発と応用 招待有り

    石川 稔

    アステラス製薬株式会社講演会 2014年4月

  46. タンパク質を特異的に分解誘導する低分子を利用した新治療戦略と低分子の標的タンパク質同定法 招待有り

    石川 稔

    第86回日本生化学会大会 シンポジウム ケミカルライブラリースクリーニング再考 アカデミアで意味あるケミカルライブラリースクリーニングを実現するために 2013年9月

  47. 細胞内レチノイン酸結合タンパク質(CRABP)を特異的に分解誘導する低分子の創製と新治療戦略 招待有り

    石川 稔

    日本レチノイド研究会第24回学術集会 若手シンポジウム 2013年8月

  48. タンパク質を特異的に分解する低分子の創製と応用 招待有り

    石川 稔

    東京大学 第17回分生研シンポジウム 2012年10月

  49. 親水性置換基導入に頼らない水溶性向上策:平面性・対称性の崩壊を目指した分子設計 招待有り

    石川 稔

    田辺三菱製薬株式会社講演会 2011年8月

  50. 新しい創薬戦略:タンパク質間相互作用の制御と親水性置換基導入に頼らない水溶性向上策 招待有り

    石川 稔

    明治薬科大学 平成22年度第2回化学系若手研究者講話 2011年2月

  51. 水溶性の優れた非ペプチド性インテグリンαvβ3/αIIbβ3デュアル拮抗薬の創製 招待有り

    石川 稔

    日本薬学会第130年会 シンポジウム 有機化学を基盤とする実践的創薬 2010年3月

  52. 新しい創薬手法の開発:タンパク質相互作用の制御と水溶性向上策 招待有り

    石川 稔

    三井化学株式会社講演会 2010年2月

︎全件表示 ︎最初の5件までを表示

産業財産権 9

  1. インテグリンαvβ3拮抗剤としてのアミノピペリジン誘導体

    石川 稔, 村上 省一, 山本 幹夫, 窪田 大, 蜂須 貢, 片野 清昭, 味戸 慶一

    産業財産権の種類: 特許権

  2. インテグリンαvβ3拮抗作用を有するα-ヒドロキシカルボン酸類新規化合物

    味戸 慶一, 八幡 直和, 石川 稔, 窪田 大, 村上 省一, 山本幹 夫, 藤島 和幸, 五味 修一, 大内 章吉

    産業財産権の種類: 特許権

  3. インテグリンαvβ3拮抗作用を有するメタ置換安息香酸誘導体

    味戸 慶一, 石川 稔, 窪田 大, 村上 省一, 山本 幹夫, 八幡 直和, 藤島 和幸, 大山 真

    産業財産権の種類: 特許権

  4. インテグリンαvβ3拮抗剤としての3-アミノピペリジン誘導体

    石川 稔, 窪田 大, 平岩 由紀子, 津島 正樹, 山本 幹夫, 八幡 直和, 黒田 千津子, 安部 允泰, 藤島 和幸, 村上 省一, 味戸 慶一

    産業財産権の種類: 特許権

  5. インテグリンαvβ3拮抗物質を含んでなる再灌流障害治療剤

    藤島 和幸, 村上 省一, 山本 幹夫, 安部 允泰, 石川 稔, 大内 章吉, 味戸 慶一

    産業財産権の種類: 特許権

  6. (4-オキソピペリジン-1-イル)安息香酸誘導体を用いたインテグリンαvβ3阻害剤の製造法

    石川 稔, 津島 正樹, 山田 拓, 窪田 大, 柳沢 由美子, 平岩 由起子, 大内 章吉, 安西 直道, 味戸 慶一

    産業財産権の種類: 特許権

  7. 2位チエニルカルバペネム誘導体

    勢津 文仁, 塩川 宗二郎, 川野 愛美, 狩野 ゆうこ, 佐藤 晋也, 佐藤 悦子, 古内 剛, 石川 誠, 石川 稔, 金田 香織, 坂巻 儀晃, 馬場 信吉, 是澤 友和

    産業財産権の種類: 特許権

  8. インテグリンαvβ3拮抗剤としてのフェニルピペラジン誘導体

    味戸 慶一, 村上 省一, 石川 稔, 山本 幹夫, 窪田 大, 五味 修一, 蜂須 貢, 片野 清昭

    産業財産権の種類: 特許権

  9. 抗血小板凝集阻害作用を有するカルボン酸誘導体

    太田 和美, 磯村 泰子, 石川 稔, 奥平 典子, 鈴木 尚, 相澤 一雅, 片野 清昭

    産業財産権の種類: 特許権

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 13

  1. プロテオスタシスの異常を是正するネオユビキチンコードの解明

    大竹史明

    2021年 ~ 2026年

  2. 疾患関連タンパク質の近接制御を基盤とした新しい創薬化学

    石川 稔

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    研究種目:Grant-in-Aid for Scientific Research (A)

    研究機関:Tohoku University

    2022年4月 ~ 2025年3月

  3. ケミカルプロテインノックダウン技術の開発と細胞制御

    内藤 幹彦, 伊藤 拓水, 石川 稔, 出水 庸介

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    2018年6月29日 ~ 2023年3月31日

    詳細を見る 詳細を閉じる

    ケミカルプロテインノックダウン技術の開発と拡充では、リガンドにデコイ核酸を利用することで転写因子の分解を可能にする核酸型SNIPERの開発に成功した。また、高活性・高選択的にプロスタグランジンD合成酵素(HPGDS)を分解誘導できる低分子型PROTACの開発に成功した。神経変性疾患の一種であるハンチントン病の原因タンパク質を分解誘導するSNIPERの構造を疎水性タグ連結化合物に改変し、この化合物が脳内移行性を示すことを示した。また共同研究によりユビキチンリガーゼとそのリガンドの結合様式を解析し、その情報を元に新たなSNIPERを合成した。標的タンパク質分解分子に利用できるE3ユビキチンリガーゼを増やすため、これまでPROTACに利用されていないE3のリガンドとのキメラ分子を合成した。難治性のすい臓がんではCRABP-IIの発現が高くゲムシタビンに耐性を示すが、CRABP-IIを分解するSNIPERが難治性すい臓がんの薬剤耐性を克服することを見出した。がん特異的融合タンパク質FGFR-TACC3を分解するSNIPERを開発し、FGFR-TACC3陽性のがん細胞に選択的な細胞死を誘導することを見出した。サリドマイドが誘導する血管新生阻害関連CRBNネオ基質の下流機構の解析では、プロテオミクスおよびトランスクリプトーム解析を行った結果、ネオ基質の下流因子を明らかにした。またCC-122のDLBCL増殖抑制効果についてもトランスクリプトーム解析により下流においてTNFαシグナリングが動くことなどが示唆された。またサリドマイド誘導体であるポマリドミドの誘導するCRBNネオ基質にPLZFおよびPLZF融合タンパク質があることを発見した。

  4. 疾患関連タンパク質のタグ化を誘導する新創薬モダリティ 競争的資金

    石川 稔

    2018年 ~ 2022年

  5. ケモテクノロジーが拓くユビキチンニューフロンティア 競争的資金

    内藤 幹彦

    2018年 ~ 2022年

  6. 細胞内アミロイドβのケミカルバイオロジー 競争的資金

    石川 稔

    2017年 ~ 2018年

  7. 標的タンパク質の機能とダイナミズムの制御に基づく難病多重薬理療法の構築

    橋本 祐一, 石川 稔, 藤井 晋也, 谷内出 友美

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research (B)

    研究機関:The University of Tokyo

    2014年4月1日 ~ 2017年3月31日

    詳細を見る 詳細を閉じる

    多くの難病の特徴は増悪因子の多重性である。よって、その効果的な治療には複数の機能と持つ化合物、すなわち多重薬理化合物、が有効なはずである。本研究課題では、(1)同時に複数の疾病増悪因子を標的とする化合物や、(2)複数の作用機序を同時に発揮しうる化合物、特に、標的タンパク質の機能制御活性に加えて存在状態の制御活性(凝集阻止や分解誘導など)を併せ持った化合物の創製研究を展開した。(1)については各種核内受容体や、エピジェネティック因子、(2)については疾病関連凝集性タンパク質を主たる対象とした。 加えて、創製した化合物の有用性を生物検定系を通じて評価し、多重薬理化合物の優位性を実験的に検証した。

  8. 化合物が導くリバース翻訳後修飾プロテオミクス 競争的資金

    石川 稔

    2013年 ~ 2017年

  9. タンパク質動的状態(ドラマタイプ)のケミカルコントロール

    橋本 祐一, 石川 稔, 青山 洋史, 杉田 和幸, 小林 久芳, 谷内出 友美, 松本 洋太郎, 三澤 隆史

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research (A)

    研究機関:The University of Tokyo

    2010年4月1日 ~ 2014年3月31日

    詳細を見る 詳細を閉じる

    タンパク質の機能や存在状態(細胞内での局在・分布や安定性・寿命)はその3次構造に依存している。したがって、特定のタンパク質の3次構造の制御は、その機能や存在状態の制御に直結する。また、特定のタンパク質の3次構造の異常に基づく多くの難治性疾患が存在する。本研究では、(1)タンパク質の3次構造を制御することによって作用を発揮する各種核内受容体リガンドの創製、(2)タンパク質の異常な3次構造に基づく細胞内局在異常を修正する化合物群の創製、ならびに(3)特定のタンパク質の生細胞内での分解を誘導する化合物群の創製、に成功するとともに、(4)関わる分子設計として共通骨格を利用する手法を提案した。

  10. 多重薬理作用によるC型肝炎の治療戦略 競争的資金

    石川 稔

    2013年 ~ 2014年

  11. タンパク質の特異的分解手法が切り拓く創薬化学の新カテゴリー 競争的資金

    石川 稔

    2011年 ~ 2012年

  12. タンパク翻訳後ノックアウト法:標的タンパク質を特異的に分解するハイブリッド小分子

    橋本 祐一, 石川 稔

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Challenging Exploratory Research

    研究機関:The University of Tokyo

    2009年 ~ 2011年

    詳細を見る 詳細を閉じる

    標的とするタンパク質に対するリガンドと、ユビキチンリガーゼに対して親和性を持つ低分子化合物とのハイブリッド分子を活用することによって、プロテインノックダウン技術を開発することができる。ユビキチンリガーゼとして、メチルベスタチンに対して特異的親和性を有するcIAP1を選択し、メチルベスタチンと各種リガンドとのハイブリッド分子を設計し、合成した。創製したハイブリッド分子は、それぞれのリガンドが標的とするタンパク質の分解を誘導し、プロテインノンクダウン法の有用性と一般性を示すことができた。

  13. 多次元同時阻害作用を有する核内受容体機能阻害薬の創製研究 競争的資金

    石川 稔

    2009年 ~ 2010年

︎全件表示 ︎最初の5件までを表示

担当経験のある科目(授業) 5

  1. 細胞機能工学 東京大学大学院農学系研究科

  2. 全学体験ゼミナール 東京大学教養学部

  3. 医薬化学II 東京大学薬学部

  4. 基礎薬科学特論II 東京大学大学院薬学系研究科

  5. ケミカルバイオロジー特論 東京大学大学院薬学系研究科