Exploring the small molecule inhibitors that specifically block the intracellular signal perturbation induced by Helicobacter pylori CagA oncoprotein

• Project/Area Number: 16K19121
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bacteriology (including mycology)
• Research Institution: The University of Tokyo
• Principal Investigator: Hayashi Takeru 東京大学, 大学院医学系研究科(医学部), 助教 (10722209)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: ヘリコバクター・ピロリ / CagA / 胃発がん / がんタンパク質 / 胃がん / ピロリ菌 / 阻害剤探索 / 感染症 / がん / トランスレーショナルリサーチ

Outline of Final Research Achievements

X-ray crystal structure analysis and biochemical analysis revealed the structural mechanism underlying the deregulation of human pro-oncogenic phosphatase SHP2 by Helicobacter pylori virulence factor CagA at the atomic level. Based on the structural information, I then explored small-molecular inhibitors that can specifically block CagA-SHP2 interaction. Chemical screening using multiple compound libraries identified several candidates of the inhibitor for CagA-mediated SHP2 deregulation. This study is expected to be a research base leading to the innovative clinical application for prevention and early intervention of gastric cancer caused by H. pylori infection.

Research Products

• [Journal Article] Differential mechanisms for SHP2 binding and activation are exploited by geographically distinct Helicobacter pylori CagA Oncoproteins. (2017)
  • Author(s): Hayashi, H., Senda, M., Suzuki, N., Nishikawa, H., Ben, C., Tang, C., Nagase, L., Inoue, K., Senda, T. and Hatakeyama, M.
  • Journal Title: Cell Rep Volume: 20 Issue: 12 Pages: 2876-2890
  • DOI: 10.1016/j.celrep.2017.08.080
  • Peer Reviewed / Open Access
• [Journal Article] Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b. (2016)
  • Author(s): Nishikawa, H., Hayashi, T., Arisaka, F., Senda, T., Hatakeyama, M.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 30031-30031
  • DOI: 10.1038/srep30031
  • Peer Reviewed / Open Access
• [Presentation] Structural insights into the mechanism underlying activation of SHP2 by the Helicobacter pylori CagA oncoprotein. (2017)
  • Author(s): Hayashi, T., Senda, M., Suzuki, N., Inoue, K., Nagase, L., Nishikawa, H., Senda, T., Hatakeyama, M.
  • Organizer: Europhosphatase 2017
  • Int'l Joint Research
• [Presentation] ピロリ菌CagAによる細胞内シグナル撹乱の構造生物学的解析 (2017)
  • Author(s): 林 剛瑠
  • Organizer: マックスプランク・東京大学統合延焼学センター ジュニアフェローセミナー
  • Invited
• [Presentation] Solution structure analysis of SHP2 in complex with the EPIYA region of Helicobacter pylori CagA (2016)
  • Author(s): 鈴木喜大、林剛瑠、千田美紀、長瀬里沙、畠山昌則、千田俊哉
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Structural insights into the mechanism underlying activation of SHP2 by the Helicobacter pylori CagA oncoprotein (2016)
  • Author(s): 林剛瑠、千田美紀、千田俊哉、畠山昌則
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Remarks] 東京大学プレスリリース：ピロリ菌がんタンパク質の1アミノ酸多型が日本人胃がん多発の背景に
  • URL: http://www.m.u-tokyo.ac.jp/news/admin/release_20170919.pdf
• [Remarks] ピロリ菌の株間で胃を傷害する強さが異なる理由
  • URL: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/why-degree-of-damage-to-stomach-differs-between-h-pylori-strains.html