Small molecules that control Hes1 oscillation

• Project/Area Number: 26560445
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: Kyoto University
• Principal Investigator: Uesugi Motonari 京都大学, 物質－細胞統合システム拠点, 教授 (10402926)
• Co-Investigator(Renkei-kenkyūsha): KAGEYAMA Ryoichiro 京都大学, ウイルス研究所, 教授 (80224369)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 化学プローブ / ケミカルバイオロジー

Outline of Final Research Achievements

Hes1 is a transcriptional repressor that plays an important role in cell differentiation. We previously isolated a potent Hes1 modulator (D8C) through high-throughput screening. A total of 176 D8C derivatives were synthesized and tested for their effects on Hes1-mediated repression. Out of these compounds, JI051 showed a 5-fold improvement in EC50 value as compared to D8C. Our mechanistic analysis revealed that JI051 induces the nuclear export of Hes1 and its corepressor TLE1 with concomitant mitochondrial release of the TLE1 protein regulator, Bit1. Target identification studies highlighted the mitochondrial protein Prohibitin 2 (PHB2) as a target for JI051. The interaction of JI051 with PHB2 appears to increase superoxide production associated with mitochondrial membrane depolarization. These results suggest that JI051 inhibits Hes1 through its PHB2-dependent nuclear export.

Research Products

• [Journal Article] A potent and site-selective agonist of TRPA1. (2015)
  • Author(s): Takaya, J., Mio, K., Shiraishi, T., Kurokawa, T., Otsuka, S., Mori, Y., Uesugi, M.
  • Journal Title: J. Am. Chem. Soc. Volume: 137 Issue: 50 Pages: 15859-15864
  • DOI: 10.1021/jacs.5b10162
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intracellular generation of a diterpene-peptide conjugate that inhibits 14-3-3-mediated interactions. (2015)
  • Author(s): Parvatkar P., Kato N., Uesugi M., Sato S., Ohkanda J.
  • Journal Title: J. Am. Chem. Soc. Volume: 137 Issue: 50 Pages: 15624-15627
  • DOI: 10.1021/jacs.5b09817
  • Peer Reviewed
• [Journal Article] Live-cell Imaging of Endogenous mRNAs with a Small Molecule (2015)
  • Author(s): Sato, S.*, Watanabe, M., Katsuda, Y., Murata, A., Wang, D. O., Uesugi M.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 54 Issue: 6 Pages: 1855-1858
  • DOI: 10.1002/anie.201410339
  • NAID: 120005619801
  • Peer Reviewed
• [Journal Article] A chemical probe that labels human pluripotent stem cells (2014)
  • Author(s): Hirata N, Nakagawa M, Fujibayashi Y, Yamauchi K, Murata A, Minami I, Tomioka M, Kondo T, Kuo TF, Endo H, Inoue H, Sato S, Ando S, Kawazoe Y, Aiba K, Nagata K, Kawase E, Chang YT, Suemori H, Eto K, Nakauchi H, Yamanaka S, Nakatsuji N, Ueda K, Uesugi M
  • Journal Title: Cell reports Volume: 6 Issue: 6 Pages: 1165-74
  • DOI: 10.1016/j.celrep.2014.02.006
  • NAID: 120005466668
  • Peer Reviewed / Open Access
• [Journal Article] Selective elimination of human pluripotent stem cells by a marine natural product derivative. (2014)
  • Author(s): Ting-Fang Kuo, Di Mao, Nao Hirata, Bilon Khambu, Yasuhisa Kimura, Eihachiro Kawase, Hiroki Shimogawa, Makoto Ojika, Norio Nakatsuji, Kazumitsu Ueda, and Motonari Uesugi
  • Journal Title: J Am Chem Soc Volume: 136 Issue: 28 Pages: 9798-9801
  • DOI: 10.1021/ja501795c
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthetic molecules that protect cells from anoikis and their use in cell transplantation (2014)
  • Author(s): Frisco-C., H.L.; Watanabe, M.; Okumura, N.; Kusamori, K.; Takemoto, N.; Takaya, J.; Sato, S.; Yamazoe, S.; Takakura, Y.; Kinoshita, S.; Nishikawa, M.; Koizumi, N.; Uesugi, M.
  • Journal Title: Angew. Chem., Int. Ed. Volume: 53 Issue: 42 Pages: 11208-11213
  • DOI: 10.1002/ange.201405829
  • Peer Reviewed
• [Journal Article] Affinity-Based Isolation of Molecular Targets of Clinically Used Drugs (2014)
  • Author(s): Sato, S., Uesugi, M.
  • Journal Title: Concepts and Case Studies in Chemical Biology Volume: 15 Pages: 221-230
  • DOI: 10.1002/9783527687503.ch15
  • Peer Reviewed
• [Presentation] Synthetic Molecules for Cell Therapy (2016)
  • Author(s): Uesugi, M.
  • Organizer: 2016 Queenstown Molecular Biology Meetings in Shanghai
  • Place of Presentation: Shanghai (China)
  • Year and Date: 2016-03-17
  • Int'l Joint Research / Invited
• [Presentation] Synthetic Molecules for Detecting and Eliminating Human Pluripotent Stem Cells (2016)
  • Author(s): Uesugi, M.
  • Organizer: ABC2016 - 6th Special Meeting on ABC Proteins
  • Place of Presentation: Innsbruck (Austria)
  • Year and Date: 2016-03-05
  • Int'l Joint Research / Invited
• [Presentation] 生理活性化合物の新しい世界 (2016)
  • Author(s): 上杉 志成
  • Organizer: 第108回分子科学フォーラム 市民公開講座
  • Place of Presentation: 岡崎コンファレンスセンター（愛知県岡崎市)
  • Year and Date: 2016-02-05
  • Invited
• [Presentation] Synthetic Molecules for Eliminating Human Pluripotent Stem Cells (2016)
  • Author(s): Uesugi, M.
  • Organizer: ACBI 2016 Jakarta Meeting
  • Place of Presentation: Jakarta (Indonesia)
  • Year and Date: 2016-01-29
  • Int'l Joint Research / Invited
• [Presentation] Synthetic Molecules for Cell Biology and Cell Therapy (2016)
  • Author(s): Uesugi, M.
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 武田薬品研修所（大阪府吹田市）
  • Year and Date: 2016-01-21
  • Int'l Joint Research / Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: Pacifichem 2015 Natural Product-based Drug Discovery
  • Place of Presentation: Honolulu(USA)
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Small Molecules That Modulate Protein Assemblies (2015)
  • Author(s): Uesugi, M.
  • Organizer: Pacifichem 2015 Synthetic Modulators of Protein-Protein Interactions
  • Place of Presentation: Honolulu(USA)
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] 細胞を操る合成化合物 (2015)
  • Author(s): 上杉 志成
  • Organizer: 岡崎統合バイオサイエンスセンター生命時空間設計研究領域 心循環シグナル研究部門公開セミナー
  • Place of Presentation: 岡崎統合バイオサイエンスセンター(愛知県岡崎市)
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] 嫌いなものにチャンスがある！：ケミカルバイオロジーとは? (2015)
  • Author(s): 上杉 志成
  • Organizer: BMB2015市民公開講座
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市)
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] Synthetic Molecules for Detecting and Eliminating Human Pluripotent Stem Cells (2015)
  • Author(s): Uesugi, M.
  • Organizer: NEA & ASIAHORCs Joint Symposium - Chemical Biology - in Okinawa
  • Place of Presentation: 沖縄科学技術大学院大学(沖縄県国頭郡)
  • Year and Date: 2015-11-08
  • Int'l Joint Research / Invited
• [Presentation] Synthetic Molecules for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: XVII NOST-Organic Chemistry Conference
  • Place of Presentation: Jaipur (India)
  • Year and Date: 2015-10-27
  • Int'l Joint Research / Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: 2015 Fall Annual Convention of Pharmaceutical Society of Korea
  • Place of Presentation: Daegu (Korea)
  • Year and Date: 2015-10-22
  • Int'l Joint Research / Invited
• [Presentation] Synthetic Molecules for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: AIMECS 2015 (10th AFMC International Medicinal Chemistry Symposium in 2015)
  • Place of Presentation: Jeju (Korea)
  • Year and Date: 2015-10-18
  • Int'l Joint Research / Invited
• [Presentation] 生理活性合成化合物のケミカルバイオロジーが開く新しい世界 (2015)
  • Author(s): 上杉 志成
  • Organizer: 日本化学会秋季事業- 第5回CSJ化学フェスタ2015
  • Place of Presentation: タワーホール船堀(東京都江戸川区)
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] Synthetic Molecules for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: IUPAC2015
  • Place of Presentation: Busan (Korea)
  • Year and Date: 2015-08-10
  • Int'l Joint Research / Invited
• [Presentation] くすりの形 (2015)
  • Author(s): 上杉 志成
  • Organizer: 京都大学化学研究所 第18回高校生のための化学
  • Place of Presentation: 京都大学宇治キャンパス（京都府宇治市)
  • Year and Date: 2015-07-25
  • Invited
• [Presentation] 細胞治療を助ける合成化合物 (2015)
  • Author(s): 上杉 志成
  • Organizer: 第52回薬剤学懇談会研究討論会
  • Place of Presentation: 瑠璃光(石川県加賀市)
  • Year and Date: 2015-07-17
  • Invited
• [Presentation] Synthetic Molecules for Cell Biology and Cell Therapy (2015)
  • Author(s): Uesugi, M.
  • Organizer: The 51th International Conference on Medicinal Chemistry (RICT 2015) - "Drug Discovery and Selection - Understanding Targets and Mechanisms"
  • Place of Presentation: Avignon (France)
  • Year and Date: 2015-07-01
  • Int'l Joint Research / Invited
• [Presentation] 細胞を操作する合成化合物 (2015)
  • Author(s): 上杉 志成
  • Organizer: 第10回理研シンポジウム：第10回有機合成化学のフロンティア
  • Place of Presentation: 理化学研究所和光事業所(埼玉県和光市)
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] Introduction of Chemical Biology (2015)
  • Author(s): Motonari Uesugi
  • Organizer: Cell Biology, Developmental Biology, and Systems Biology Course Meeting
  • Place of Presentation: Kyoto (Japan)
  • Year and Date: 2015-02-13
  • Invited
• [Presentation] 細胞を操作・検出する合成小分子化合物 (2015)
  • Author(s): 上杉 志成
  • Organizer: 近畿化学協会機能性色素部会 第88回例会「未来をつくる機能性色素･･･その技術と応用･･･」
  • Place of Presentation: 大阪科学技術センター（大阪市）
  • Year and Date: 2015-02-12
  • Invited
• [Presentation] Introduction to Chemical Biology (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Asian Chemical Biology Initiative 2014 Kota Kinabalu Meeting: Open Tutorial Lectures
  • Place of Presentation: Kota Kinabalu (Malaysia)
  • Year and Date: 2014-12-19
  • Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Institute of Molecular and Cell Biology Seminar
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2014-12-17
  • Invited
• [Presentation] Small Molecule Tools for Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: The 3rd Asian Chemical Biology Conference
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2014-12-15 – 2014-12-17
  • Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Nanjing University School of Life Sciences Seminar
  • Place of Presentation: Nanjing (China)
  • Year and Date: 2014-11-26
  • Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Asian Chemical Biology Initiative 2014 Hangzhou Meeting
  • Place of Presentation: Hangzhou (China)
  • Year and Date: 2014-11-22 – 2014-11-25
  • Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Chinese National Compound Library 2014 Seminar Series
  • Place of Presentation: Shanghai (China)
  • Year and Date: 2014-11-21
  • Invited
• [Presentation] Small Molecules That Detect and Remove Human Pluripotent Stem Cells (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Sino-Japan Workshop on Chemical Biology
  • Place of Presentation: Beijing (China)
  • Year and Date: 2014-10-10 – 2014-10-13
  • Invited
• [Presentation] Small Molecule Tools That Detect and Remove Human Pluripotent Stem Cells (2014)
  • Author(s): Motonari Uesugi
  • Organizer: China-Japan Joint Seminar on Histochemistry and Cytochemistry
  • Place of Presentation: Nagano (Japan)
  • Year and Date: 2014-09-28 – 2014-09-29
  • Invited
• [Presentation] Small Molecule Tools for Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Forth Norman Bethune International Forum on Medical Sciences
  • Place of Presentation: Jilin (China)
  • Year and Date: 2014-09-20 – 2014-09-22
  • Invited
• [Presentation] 生理活性合成化合物の新しい世界 (2014)
  • Author(s): 上杉 志成
  • Organizer: 第31回有機合成化学セミナー
  • Place of Presentation: 休暇村志賀島（福岡市）
  • Year and Date: 2014-09-17 – 2014-09-19
  • Invited
• [Presentation] 細胞を操作・検出する合成小分子化合物 (2014)
  • Author(s): 上杉 志成
  • Organizer: 東京農工大学工学府講演会
  • Place of Presentation: 東京農工大学(小金井市)
  • Year and Date: 2014-07-25
  • Invited
• [Presentation] 細胞治療を助ける合成化合物 (2014)
  • Author(s): 上杉 志成
  • Organizer: 創薬科学研究センターシンポジウム2014有機合成によるアンメット・メディカルニーズに応える医薬品開発
  • Place of Presentation: 立命館大学（草津市）
  • Year and Date: 2014-07-11
  • Invited
• [Presentation] Introduction of Chemical Biology & Small-Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: Asian Chemical Biology Initiative-Sponsored Lectures
  • Place of Presentation: Hanoi (Vietnam)
  • Year and Date: 2014-07-01
  • Invited
• [Presentation] Small Molecule Tools for Cell Biology and Cell Therapy (2014)
  • Author(s): Motonari Uesugi
  • Organizer: The University of Tokyo School of Science 1527th Seminar
  • Place of Presentation: Tokyo (Japan)
  • Year and Date: 2014-06-20
  • Invited
• [Presentation] 脂質合成を遮断する小分子化合物 (2014)
  • Author(s): 上杉 志成
  • Organizer: 小野医学研究財団 第25回研究成果発表会
  • Place of Presentation: 千里ライフサイエンスセンター(豊中市)
  • Year and Date: 2014-06-07
  • Invited
• [Presentation] Small Molecules that Block Fat Synthesis (2014)
  • Author(s): Motonari Uesugi
  • Organizer: RIKEN-Max Planck Joint Research Center for Systems Chemical Biology 3rd Annual Symposium
  • Place of Presentation: Kreuth (Germany)
  • Year and Date: 2014-05-21 – 2014-05-24
  • Invited
• [Presentation] 細胞を操作・検出する合成小分子化合物 (2014)
  • Author(s): 上杉 志成
  • Organizer: 「生物医工学サロン」第55回集会
  • Place of Presentation: 京都大学（京都市）
  • Year and Date: 2014-05-12
  • Invited
• [Book] ビオチン化体を利用した生化学的標的タンパク質精製法 (2015)
  • Author(s): 佐藤慎一、勝田陽介、上杉志成
  • Total Pages: 5
  • Publisher: 化学同人
• [Remarks] 京都大学iCeMS・化学研究所 上杉研究室
  • URL: http://www.scl.kyoto-u.ac.jp/~uesugi/