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2013 Fiscal Year Final Research Report

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

Research Project

  • PDF
Project/Area Number 23590336
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General medical chemistry
Research InstitutionKobe 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

    (18 results)

All 2014 2013 2012 2011 2009 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (3 results) (of which Invited: 1 results) Book (1 results) Remarks (3 results) Patent(Industrial Property Rights) (6 results) (of which Overseas: 3 results)

  • [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 activity2013

    • 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 interaction2013

    • 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 mutants2012

    • 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 Conformers2011

    • 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 mouse2013

    • 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 interaction2013

    • 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 conformers2012

    • 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

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Published: 2015-07-16  

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