Small molecules that induce atypical ubiquitinations

• Project/Area Number: 19K16326
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Tohoku University
• Principal Investigator: Tomoshige Shusuke 東北大学, 生命科学研究科, 助教 (50822524)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 疎水性タグ / mHtt / タンパク質分解 / ユビキチン化 / K63型ユビキチン / IAP / RIP1 / K63結合型ユビキチン化

Outline of Research at the Start

ユビキチン（Ub）化は翻訳後修飾の一種であり、Ub の結合様式によって様々な機能を発現する。特にタンパク質の分解シグナルとして働くUb 化がよく知られているが、その他の特殊なUb 化については不明な点が多い。しかし、特殊なUb 化は様々な生命現象や疾患に関与することが示唆されており、その機能解析が求められる。そこで本研究では、特殊なUb 化の機能解析に有用なケミカルツールの開発を志向し、標的タンパク質に特殊なUb 化を誘導する小分子を創製する。過去に標的タンパク質のUb 化と分解を誘導する小分子を創製しており、その知見を活かして特殊なUb 化誘導剤の設計・合成および活性評価を行う。

Outline of Final Research Achievements

Ubiquitination, a posttranslational modification, has been shown to have variety in its linkage type. Here I aimed to generate compounds able to induce atypical ubiquitinations. Compounds that can display hydrophobic structure on protein surface were synthesized and are found to mediate targeted degradation of mHtt via ubiquitin-proteasome system. The results were reported in an international conference and were published in an international academic journal.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた化合物は通常のユビキチン化経路とは異なる経路でユビキチン化を誘導しタンパク質を分解するため、特殊なユビキチン化を誘導している可能性が考えられる。本化合物についてさらなる解析が必要だが、特殊なユビキチン化に関する研究を支援するケミカルツールになりうる。
また、化合物によって減少したmHttは神経変性疾患の原因となるタンパク質であり。この化合物は脳移行性も示したことから、神経変性疾患の新規治療戦略の提案につながった。

Research Products

• [Journal Article] Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties (2022)
  • Author(s): Hirai Keigo、Yamashita Hiroko、Tomoshige Shusuke、Mishima Yugo、Niwa Tatsuya、Ohgane Kenji、Ishii Mayumi、Kanamitsu Kayoko、Ikemi Yui、Nakagawa Shinsaku、Taguchi Hideki、Sato Shinichi、Hashimoto Yuichi、Ishikawa Minoru
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 13 Issue: 3 Pages: 396-402
  • DOI: 10.1021/acsmedchemlett.1c00500
  • Peer Reviewed
• [Journal Article] PROTACs and Other Chemical Protein Degradation Technologies for the Treatment of Neurodegenerative Disorders (2021)
  • Author(s): Shusuke Tomoshige, Minoru Ishikawa
  • Journal Title: Angewandte Chemie International Edition Volume: 60 Issue: 7 Pages: 3346-3354
  • DOI: 10.1002/anie.202004746
  • Peer Reviewed
• [Journal Article] Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs (2020)
  • Author(s): Ishikawa Minoru、Tomoshige Shusuke、Demizu Yosuke、Naito Mikihiko
  • Journal Title: Pharmaceuticals Volume: 13 Issue: 4 Pages: 74-74
  • DOI: 10.3390/ph13040074
  • Peer Reviewed / Open Access
• [Journal Article] Investigation on the Epoxidation of Piperitenone, and Structure-activity Relationships of Piperitenone Oxide for Differentiation-inducing Activity (2020)
  • Author(s): R Sato, A Sasaki, Y Mori, M Komai, S Kamo, M Onuki, T Seki, Z Kawabe, S Miyajima, S Tomoshige, T Kawasaki, S Sato, T Nakamura, N Kubo, S Takeda, S Date, S Okamoto, P Boonyaritthongchai, K Thirapanmethee, M T Chomnawang, B Bongcheewin, T L Nguyen, H L T Nguyen, H T Le, Y Nakamura, K Kuramochi
  • Journal Title: Journal of Oleo Science Volume: 69 Issue: 8 Pages: 951-958
  • DOI: 10.5650/jos.ess19278
  • NAID: 130007885409
  • ISSN: 1345-8957, 1347-3352
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis and Cytotoxic Evaluation of N-Alkyl-2-halophenazin-1-ones (2020)
  • Author(s): Kohatsu Haruki、Kamo Shogo、Furuta Masateru、Tomoshige Shusuke、Kuramochi Kouji
  • Journal Title: ACS Omega Volume: 5 Issue: 42 Pages: 27667-27674
  • DOI: 10.1021/acsomega.0c04253
  • Peer Reviewed / Open Access
• [Journal Article] Isolation, synthesis, and biological activities of a bibenzyl from Empetrum nigrum var. japonicum. (2020)
  • Author(s): Oka. S, Kuniba. R, Tsuboi. N, Tsuchida. S, Ushida. K, Tomoshige. S, Kuramochi. K.
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84(1) Issue: 1 Pages: 31-36
  • DOI: 10.1080/09168451.2019.1662279
  • Peer Reviewed
• [Journal Article] Application of protein knockdown strategy targeting β-sheet structure to multiple disease-associated polyglutamine proteins (2020)
  • Author(s): Yamashita Hiroko、Tomoshige Shusuke、Nomura Sayaka、Ohgane Kenji、Hashimoto Yuichi、Ishikawa Minoru
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 28 Issue: 1 Pages: 115175-115175
  • DOI: 10.1016/j.bmc.2019.115175
  • Peer Reviewed
• [Journal Article] Synthesis and structural revision of an indanone isolated from Triphyophyllum peltatum (2020)
  • Author(s): Ishii Yunosuke、Ota Motohiro、Kamo Shogo、Tomoshige Shusuke、Tsubaki Kazunori、Kuramochi Kouji
  • Journal Title: Tetrahedron Letters Volume: 61 Issue: 7 Pages: 151494-151494
  • DOI: 10.1016/j.tetlet.2019.151494
  • Peer Reviewed
• [Journal Article] Dimerizations of 2-bromo-3-methyl-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone in tetra-n-butylammonium bromide (2020)
  • Author(s): Onuki Mai、Ota Motohiro、Otokozawa Shoya、Kamo Shogo、Tomoshige Shusuke、Tsubaki Kazunori、Kuramochi Kouji
  • Journal Title: Tetrahedron Volume: 76 Issue: 6 Pages: 130899-130899
  • DOI: 10.1016/j.tet.2019.130899
  • Peer Reviewed
• [Journal Article] Synthesis, antibacterial and cytotoxic evaluation of flavipucine and its derivatives. (2019)
  • Author(s): Kusakabe Y, Mizutani S, Kamo S, Yoshimoto T, Tomoshige S, Kawasaki T, Takasawa R, Tsubaki K, Kuramochi K.
  • Journal Title: Bioorg Med Chem Lett. Volume: 29 Issue: 11 Pages: 1390-1394
  • DOI: 10.1016/j.bmcl.2019.03.034
  • Peer Reviewed
• [Journal Article] Unified Approach toward Syntheses of Juglomycins and Their Derivatives (2019)
  • Author(s): Yoshioka Kai、Kamo Shogo、Hosaka Keisuke、Sato Ryohei、Miikeda Yuma、Manabe Yuri、Tomoshige Shusuke、Tsubaki Kazunori、Kuramochi Kouji
  • Journal Title: ACS Omega Volume: 4 Issue: 7 Pages: 11737-11748
  • DOI: 10.1021/acsomega.9b01376
  • Peer Reviewed / Open Access
• [Journal Article] Total Syntheses of Pyocyanin, Lavanducyanin, and Marinocyanins A and B (2019)
  • Author(s): Kohatsu Haruki、Kamo Shogo、Tomoshige Shusuke、Kuramochi Kouji
  • Journal Title: Organic Letters Volume: 21 Issue: 18 Pages: 7311-7314
  • DOI: 10.1021/acs.orglett.9b02601
  • Peer Reviewed
• [Journal Article] Synthetic and Biological Studies of Juglorubin and Related Naphthoquinones (2019)
  • Author(s): Kamo Shogo、Saito Tatsuo、Kusakabe Yasuha、Tomoshige Shusuke、Uchiyama Masanobu、Tsubaki Kazunori、Kuramochi Kouji
  • Journal Title: The Journal of Organic Chemistry Volume: 84 Issue: 21 Pages: 13957-13966
  • DOI: 10.1021/acs.joc.9b02119
  • Peer Reviewed
• [Journal Article] Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication (2019)
  • Author(s): Kamata Mai、Takeuchi Toshifumi、Hayashi Ei、Nishioka Kazane、Oshima Mizuki、Iwamoto Masashi、Nishiuchi Kota、Kamo Shogo、Tomoshige Shusuke、Watashi Koichi、Kamisuki Shinji、Ohrui Hiroshi、Sugawara Fumio、Kuramochi Kouji
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84 Issue: 2 Pages: 217-227
  • DOI: 10.1080/09168451.2019.1673696
  • Peer Reviewed
• [Presentation] 脳移行性改善を指向したPROTACから疎水性タグへの構造展開 (2022)
  • Author(s): 平井景梧, 山下博子, 友重秀介, 三島祐悟, 佐藤伸一, 橋本祐一, 石川稔
  • Organizer: 日本薬学会第142年会
• [Presentation] 疎水性タグ法による凝集タンパク質のケミカルノックダウン (2021)
  • Author(s): 平井景梧, 山下博子, 三島祐悟, 友重秀介, 佐藤伸一, 橋本祐一, 石川稔
  • Organizer: 新学術領域ケモユビキチン若手発表会
• [Presentation] Conversion of A PROTAC Mutant Huntingtin Degrader into Small-molecule Hydrophobic Tags Focusing on Druglike Properties (2021)
  • Author(s): Keigo Hirai, Hiroko Yamashita, Shusuke Tomoshige, Yugo Mishima, Kenji Ohgane, Shinichi Sato, Yuichi Hashimoto, Minoru Ishikawa
  • Organizer: 13th AFMC INTERNATIONAL MEDICINAL CHEMISTRY SYMPOSIUM (AIMECS2021)
  • Int'l Joint Research
• [Presentation] フェナジノン類の網羅的合成法と活性・物性評価 (2021)
  • Author(s): 加茂翔伍，古波津春希，古田将照，細貝拓也，友重秀介，大金賢司，倉持幸司
  • Organizer: 日本農芸化学会2021年度大会
• [Presentation] 新規修飾剤開発によるチロシン残基選択的修飾 (2021)
  • Author(s): 宮野翔伍，友重秀介，石川稔，佐藤伸一
  • Organizer: 日本薬学会第141年会
• [Presentation] 疎水性タグ法による凝集性タンパク質のケミカルノックダウン (2021)
  • Author(s): 平井景梧，山下博子，友重秀介，佐藤伸一，橋本祐一，石川稔
  • Organizer: 日本薬学会第141年会
• [Presentation] Ru錯体担持アフィニティービーズを用いた抗体のFc領域選択的ヒスチジン残基修飾法の開発 (2021)
  • Author(s): 中根啓太，丹羽達也，對馬理彦，田口英樹，友重秀介，中村浩之，石川稔，佐藤伸一
  • Organizer: 日本薬学会第141年会
• [Presentation] Crystal structure analysis of BIR3 domain of ubiquitin ligase in complex with its specific ligand (2020)
  • Author(s): Makoto Okabe, Takeshi Yokoyama, Shusuke Tomoshige, Tomohisa Ogawa, Minoru Ishikawa, Yoshikazu Tanaka
  • Organizer: 第20回日本蛋白質科学会年会
• [Presentation] Crystal structure analysis of BIR3 domain of ubiquitin ligase in complex with its specific ligand for designing potent ligand (2020)
  • Author(s): Makoto Okabe, Shinichi Sato, Takeshi Yokoyama, Shusuke Tomoshige, Minoru Ishikawa, Yoshikazu Tanaka
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Efficient Synthesis of Neoechinulin B and Its Derivatives (2019)
  • Author(s): Kota Nishiuchi, Shusuke Tomoshige, Koichi Watashi, Kouji Kuramochi
  • Organizer: International Congress on Pure & Applied Chemistry (ICPAC Yangon 2019)
  • Int'l Joint Research
• [Presentation] Blugecin A Lowers Imipenem MICs in Clinical MDR Acinetobacter baumannii (ACB) Strains (2019)
  • Author(s): Marion J. Skalweit, Laura J. Rojas, Robert A. Bonomo, David A. Dik, Shusuke Tomoshige, Shahriar Mobashery
  • Organizer: IDWeek2019
• [Presentation] Plakevulin A両エナンチオマーの細胞毒性評価と標的タンパク質の探索 (2019)
  • Author(s): 古田将照, 樺澤美咲, 友重秀介, 大和屋健二, 中田一弥, 倉持幸司
  • Organizer: 日本農芸化学会関東支部大会2019年度大会
• [Presentation] フェナジノン天然物群の全合成 (2019)
  • Author(s): 古波津春樹, 加茂翔伍, 友重秀介, 倉持幸司
  • Organizer: 第61回天然有機化合物討論会
• [Presentation] Plakevulin Aの標的タンパク質の探索 (2019)
  • Author(s): 古田将照，樺澤美咲，齋藤（倉持）史代，友重秀介，大和屋健二，中田一弥，小林進，倉持幸司
  • Organizer: 第34回農薬デザイン研究会
• [Presentation] 1,4-ナフトキノン類の新規骨格転位反応を利用した天然物の合成と構造の訂正 (2019)
  • Author(s): 石井優之介、太田元博、友重秀介、倉持幸司
  • Organizer: 第34回農薬デザイン研究会
• [Presentation] フェナジノン骨格の簡便合成法の開発と天然物全合成への応用 (2019)
  • Author(s): 古波津春樹, 加茂翔伍, 友重秀介, 倉持幸司
  • Organizer: 第37回メディシナルケミストリーシンポジウム
• [Presentation] イオン性液体中での1,4-ナフトキノン類の特異な二量化反応 (2019)
  • Author(s): 大貫真依, 太田元博, 男澤翔矢, 加茂翔伍, 友重秀介, 椿一典, 倉持幸司
  • Organizer: 第37回メディシナルケミストリーシンポジウム