Development of anti-cancer drugs having Ras-Raf-binding inhibitory activity

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590336
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kobe University
• Principal Investigator: SHIMA fumi 神戸大学, 医学(系)研究科(研究院), 准教授 (60335445)
• Co-Investigator(Renkei-kenkyūsha): TAMURA Atsuo 神戸大学, 大学院理学研究科, 准教授 (90273797)
• Project Period (FY): 2011 – 2013
• Keywords: インシリコ / 創薬 / Ras癌遺伝子 / シグナル伝達 / がん / 低分子量G蛋白質

Research Abstract

ras proto-oncogene products Ras, is a member of small GTPases, which is frequently activated in a wide variety of human cancers, making them promising anti-cancer drug targets. Based on the structural information on the specific surface pocket found in the GTP-bound form of Ras proteins (Ras-GTP), we have performed the compound screening in a large scale, and succeeded in the discovery of the novel compounds (Kobe0065 and its analogues) which exhibited a significant anti-tumor activity in animal models. The compound-binding to Ras-GTP potently restrained Ras activities in vitro and in vivo, by the direct binding inhibition of Ras-GTP with the downstream effectors and also with the upstream regulators. Moreover, they showed an anti-metastatic activity on cancer cells, which is not found in the marketed anti-cancer drugs.

Research Products

• [Journal Article] rasがん遺伝子産物の新規立体構造情報を利用した分子標的がん治療薬の開発 (2014)
  • Author(s): 島扶美, 熊坂崇, 松本篤幸, 吉川陽子, 山本雅貴, 片岡徹
  • Journal Title: 日本放射光学会誌放射光 Volume: 27(1) Pages: 3-9
  • Peer Reviewed
• [Journal Article] Structure-based drug design of small-molecule Ras inhibitors having anti-tumor activity (2013)
  • Author(s): Shima, F., Kataoka, T
  • Journal Title: SPring-8 Resear ch Frontiers Volume: (in press)
  • Peer Reviewed
• [Journal Article] In silico discovery of novel small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction (2013)
  • Author(s): Shima, F., Yoshikawa, Y., Ye, M., Araki, M., Matsumoto, S., Liao, J., Hu, L., Sugimoto, T., Ijiri, Y., Takeda, A., Nishiyama, Y., Sato, C., Muraoka, S., Tamura, A., Osoda, T., Tsuda, K., Miyakawa, T., Fukunishi, H., Shimada, J., Kumasaka, T., Yamamoto, M., Kataoka, T.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110(20) Pages: 8182-8187
  • Peer Reviewed
• [Journal Article] Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants (2012)
  • Author(s): Muraoka S, Shima F, Araki M, Inoue T, Yoshimoto A, Ijiri Y, Seki N, Tamura A, Kumasaka T, Yamamoto M, Kataoka T.
  • Journal Title: FEBS Lett Volume: 586 Pages: 1715-1718
  • Peer Reviewed
• [Journal Article] Solution Structure of the State 1 Conformer of GTP-bound H-Ras Protein and Distinct Dynamic Properties between the State 1 and State 2 Conformers (2011)
  • Author(s): Araki, M., Shima, F., Yoshikawa, Y., Muraoka, S., Ijiri, Y., Nagahara, Y., Shirono, T., Kataoka, T., Tamura A.
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 39644-39653
  • Peer Reviewed
• [Presentation] Analysis of the mechani sm underlying the anti-metastatic action of R as inhibitors by using a lung metastatic mod el mouse (2013)
  • Author(s): Osamu Takano, Yoko Yoshikawa, Fumi Shima, Tohru Kataoka
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] In silico discovery of novel Ras inhibitors that display anti-tumor activity by blocking the Ras-effector interaction (2013)
  • Author(s): Shima F
  • Organizer: WINPTech 2012
  • Place of Presentation: 神戸大学統合研究拠点(兵庫県)
  • Year and Date: 2013-02-19
  • Invited
• [Presentation] Solution structure of the state 1 conformer of GTP-bound H-Ras protein and distinct dynamic properties between the state 1 and state 2 conformers (2012)
  • Author(s): Araki M, Shima F, Yoshikawa Y, Muraoka S, Ijiri Y, Nagahara Y, Shirono T, Tamura A, Kataoka T
  • Organizer: Biophysical Society 56^<th> Annual Meeting
  • Place of Presentation: Pos-L1 SAN DIEGO, CALIFORNIA, USA(ポスター)
  • Year and Date: 20120200
• [Book] Discovery of small-molecule Ras inhibitors that display antitumor activity by in terfering with Ras•GTP-effector interaction.Inhibitors of the R as superfamily G-proteins (Tamanoi, F. and Der, C. J., eds. Elsevier) (2013)
  • Author(s): Shima, F., Yoshikawa, Y., Matsumoto, S., Kataoka, T.
  • Total Pages: 1-23
  • Publisher: The Enzymes
• [Remarks] 所属研究科のホームページ
  • URL: http://www.med.kobe-u.ac.jp/molbiol/index.html
• [Remarks] 研究成果のハイライト記事
  • URL: http://www.nature.com/nrc/journal/v13/n6/full/nrc3533.html
• [Remarks]
  • URL: http://www.spring8.or.jp/ja/news_publications/press_release/2013/130430_2/
• [Patent(Industrial Property Rights)] Ras機能阻害作用を有するチオキソチアゾリジン誘導体 (2012)
  • Inventor(s): 片岡徹, 島扶美, 閨正博, 笹原大輔
  • Industrial Property Rights Holder: 神戸大学, 神戸天然物化学株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PTC/JP2012/061908
  • Filing Date: 2012-05-09
• [Patent(Industrial Property Rights)] Ras部分ポリペプチド含有水溶液及び機能阻害剤のスクリーニング方法(Aqueous Solution Containing Partial Ras Polypeptide and Method For Screening Inhibitor of Ras Function) (2012)
  • Inventor(s): 片岡徹, 島扶 美, 田村厚夫 , 荒木望嗣
  • Industrial Property Rights Holder: 神戸大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP2012/052078
  • Filing Date: 2012-01-31
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶(MUTANT RAS POLYPEPTYDE CRYSTAL) (2012)
  • Inventor(s): 片岡徹, 島扶美, 田村厚夫, 熊坂崇
  • Industrial Property Rights Holder: 神戸大学, 高輝度光科学研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: US13/383835
  • Filing Date: 2012-01-12
• [Patent(Industrial Property Rights)] Ras機能阻害作用を有するチオキソチアゾリジン誘導体 (2011)
  • Inventor(s): 片岡徹, 島扶美, 閨正博, 笹原大輔
  • Industrial Property Rights Holder: 神戸大学, 神戸天然物化学株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2011-105613
  • Filing Date: 2011-05-10
  • Overseas
• [Patent(Industrial Property Rights)] Ras部分ポリペプチド含有水溶液及び機能阻害剤のスクリーニング方法(Aqueous Solution Containing Partial Ras Polypeptide and Method For Screening Inhibitor of Ras Function) (2011)
  • Inventor(s): 片岡徹, 島扶 美, 田村厚夫 , 荒木望嗣
  • Industrial Property Rights Holder: 神戸大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2011-023695
  • Filing Date: 2011-02-07
  • Overseas
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶(MUTANT RAS POLYPEPTYDE CRYSTAL) (2009)
  • Inventor(s): 片岡徹, 島扶美, 田村厚夫, 熊坂崇
  • Industrial Property Rights Holder: 神戸大学, 高輝度光科学研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2009-165717
  • Filing Date: 2009-07-14
  • Overseas