Anti-cancer drug design targeting a novel tertiary structure of ras oncogene product

• Project/Area Number: 20590280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kobe University
• Principal Investigator: SHIMA Fumi Kobe University, 大学院・医学研究科, 講師 (60335445)
• Co-Investigator(Renkei-kenkyūsha): KUMASAKA Takashi 高輝度光科学研究センター, 利用研究促進部門, 副主席研究員 (30291066)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: インシリコ / 創薬 / rasがん遺伝子 / シグナル伝達 / がん / 低分子量G蛋白質 / Ras癌遺伝子 / 癌 / ras癌遺伝子

Research Abstract

GTP-bound form of ras oncogene product Ras exhibits dynamic equilibrium between two interconverting conformations, "inactive" state 1 and "active" state 2. Based on a novel tertiary structure of Ras-GTP, we have performed in silico and in vitro screening for low molecular weight compounds which inhibit Ras function. Consequently, we have succeeded in identification of several hit compounds which specifically bind and inhibit Ras function in vitro and in vivo.

Research Products

• [Journal Article] Critical Roles of Interactions Among Switch I-preceding Residues and Between Switch II and Its Neighboring・-helix on Conformational Dynamics of the GTP-bound Ras Family Small GTPases. (2011)
  • Author(s): Matsumoto, K., Shima, F., Muraoka, S., Araki, M., Hu, L., Ijiri, Y., Hirai, R., Yoshioka, T., Kumasaka, T., Yamamoto, M., Tamura, A., Kataoka, T.
  • Journal Title: J.Biol.Chem. 286(in press.)
  • Peer Reviewed
• [Journal Article] Critical Roles of Interactions Among Switch I-preceding Residues and Between Switch II and Its Neighboring α-helix on Conformational Dynamics of the GTP-bound Ras Family Small GTPases. (2011)
  • Author(s): Matsumoto, et al.
  • Journal Title: J.Biol.Chem. Volume: 286(in press)
  • Peer Reviewed
• [Journal Article] Structural basis for conformational dynamics of GTP-bound Ras protein. (2010)
  • Author(s): Shima, F., Ijiri, Y., Muraoka, S., Liao, J., Ye, M., Araki, M., Matsumoto, K., Yamamoto, N., Sugimoto, T., Yoshikawa, Y., Kumasaka, T., Yamamoto, M., Tamura, A., Kataoka, T.
  • Journal Title: J.Biol.Chem. 285(29) Pages: 22696-22705
  • Peer Reviewed
• [Journal Article] Structural basis for conformational dynamics of GTP-bound Ras protein. (2010)
  • Author(s): Shima, et al.
  • Journal Title: J.Biol.Chem. Volume: 285 Pages: 22696-22705
  • Peer Reviewed
• [Journal Article] Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome. (2009)
  • Author(s): Kobayashi, T., Hori, Y., Ueda, N., Kajiho, H., Muraoka, S., Shima, F., Kataoka, T., Kontani, K., Katada, T.
  • Journal Title: Biochem Biophys Res Commun. 381(3) Pages: 439-442
  • Peer Reviewed
• [Journal Article] Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome. (2009)
  • Author(s): Kobayashi T, Hori Y, Ueda N, Kajiho H, Muraoka S, Shima F, Kataoka T, Kontani K, Katada T
  • Journal Title: Biochem Biophys Res Commun. 381 Pages: 439-442
  • Peer Reviewed
• [Journal Article] Biochemical Characterization of Missense Mutations in the Arf/Arl-Family Small GTPase Arl6 Causing Bardet-Biedl Syndrome (2009)
  • Author(s): Kobayashi T, Hori Y, Ueda N, Kajiho H, Muraoka S, Shima F, Kataoka T, Kontani K, Katada T.
  • Journal Title: Biochem Biophys Res Commun. (In press : 2009 Feb 20. [Epub ahead of print])
  • Peer Reviewed
• [Presentation] New strategy for development of anti-cancer drugs targeting the ras oncogene products. (2011)
  • Author(s): 片岡徹、島扶美
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪府)(招待講演)
  • Year and Date: 2011-09-23
• [Presentation] Molecular mechanism of conformational transition of GTP-bound Ras revealed by the crystal structure analysis of M-Ras mutants. (2010)
  • Author(s): 松本耕祐, 他
  • Organizer: BMB2010(第33回日本分子生物学会年回・第83回日本生化学会大会合同大会)
  • Place of Presentation: 神戸国際展示場(兵庫県)
  • Year and Date: 2010-12-08
• [Presentation] Molecular mechanism of conformational transition of GTP-bound Ras revealed by the crystal structure analysis of M-Ras mutants (2010)
  • Author(s): 松本耕祐、島扶美、村岡真、井尻悠一、市川晋也、荒木望嗣、熊坂崇、田村厚夫、片岡徹
  • Organizer: BMB2010(第33回日本分子生物学会年回・第83回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] New strategy for development of anti-cancer drugs targeting the ras oncogene products(指定演題・モーニングレクチャー) (2010)
  • Author(s): 片岡徹、島扶美
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] GTP結合型Rasの構造遷移における分子メカニズムの解析 (2009)
  • Author(s): 井尻悠一, 島扶美, 村岡真, 廖静伶, 松本耕祐, 荒木望嗣, 熊坂崇, 田村厚夫, 片岡徹
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] 出芽酵母の低分子量Gタンパク質Ras2のX線結晶構造解析 (2009)
  • Author(s): 村岡真, 島扶美, 廖静伶, 片岡徹
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] GTP結合型Rasの構造遷移における分子メカニズムの解析(ポスター発表) (2009)
  • Author(s): 井尻悠一、島扶美、村岡真、廖静伶、松本耕祐、荒木望嗣、熊坂崇、田村厚夫、片岡徹
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] 出芽酵母の低分子量Gタンパク質Ras2のX線結晶構造解析(ポスター発表) (2009)
  • Author(s): 村岡真、島扶美、廖静伶、片岡徹
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] Structural analysis of the novel state1 conformation of Ras protein(ポスター発表) (2009)
  • Author(s): 松本耕祐, 島扶美, 村岡真, 廖静伶, 井尻悠一, 片岡徹
  • Organizer: 膜生物学グローバルCOE第3回ワークショップ
  • Place of Presentation: 兵庫県・淡路
• [Presentation] GTP結合型H-Rasの高次構造多型性とエフェクターの新規認識機構(ポスター発表) (2008)
  • Author(s): 関伸章、村岡真、荒木望嗣、吉本梓希子、島扶美、田村厚夫, 片岡徹
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] New strategy to develop Ras specific inhibitors based on conformational equilibriumof Ras oncoprotein(ポスター発表) (2008)
  • Author(s): Kousuke Matsumoto, Fumi Shima, Jingling Liao, Shin Muraoka, Tomoko Inoue, Min Ye, Takeshi Sugimoto, Yoko Yoshikawa, Moto Hiramatsu, Tohru Kataoka
  • Organizer: 第3回グローバルCOE研究討論会兼グローバルCOE第2回ワークショップ
  • Place of Presentation: 神戸
• [Presentation] New strategy to develop Ras specific inhibitors(ポスター発表) (2008)
  • Author(s): Moto Hiramatsu, Fumi Shima, Yoko Yoshikawa, Shin Muraoka, Satomi Kaizawa, Min Ye, Takeshi Sugimoto, Jingling Liao, Kousuke Matsumoto, Tohru Kataoka,
  • Organizer: 第3回グローバルCOE研究討論会兼グローバルCOE第2回ワークショップ
  • Place of Presentation: 神戸
• [Remarks] ホームページ等
  • URL: http://www.med.kobe-u.ac.jp/molbiol/index.html
• [Patent(Industrial Property Rights)] Ras機能阻害剤のスクリーニング方法 (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 Number: 2011-023695
  • Filing Date: 2011-02-07
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶(MUTANT RAS POLYPEPTYDE CRYSTAL) (2010)
  • Inventor(s): 片岡徹、島扶美、田村厚夫、熊坂崇
  • Industrial Property Rights Holder: 国立大学法人神戸大学、財団法人高輝度光科学研究センター
  • Filing Date: 2010-07-13
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶 (2009)
  • Inventor(s): 片岡徹、島扶美、田村厚夫、熊坂崇
  • Industrial Property Rights Holder: 神戸大学、財団法人高輝度光科学研究センター
  • Industrial Property Number: 2009-165717
  • Filing Date: 2009-07-14