Creation of novei anticancer lead compounds targeting the allosteric site of c-Met kinase

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08327
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo University of Science
• Principal Investigator: Tanuma Sei-ichi 東京理科大学, 研究推進機構総合研究院, 教授 (10142449)
• Co-Investigator(Kenkyū-buntansha): 高澤 涼子 東京理科大学, 薬学部薬学科, 講師 (10398828) ; 佐藤 聡 東京理科大学, 薬学部薬学科, 講師 (40530663)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 癌 / Met / チロシンキナーゼ / キナーゼ阻害剤 / in silico分子設計 / ペプチド / アポトーシス

Outline of Final Research Achievements

c-Met kinase, an oncogenic c-Met gene product, is known to involved in the many step of cancer growth and development. We have previously found an inhibitory protein against c-Met kinase, and revealed it to bind to the allosteric site of c-Met kinase. Furthermore, the mimetic inhibitory peptide (Vpep) was designed. By the in silico analysis of the binding mode of Vpep in c-Met, we could design Vpep mimetic small molecules (Ai : Allosteric inhibitor) by our COSMOS method. Interestingly, among them, Ai1 was found to enhance the inhibitory activities of c-Met catalytic inhibitors (Ci).

Free Research Field

生化学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

分子標的抗癌治療薬として、これまで腫瘍特異的なKinaseの活性を阻害するものが多く開発されてきた。しかし、そのほとんどはATP結合(Catalytic)部位への結合活性に有しており、他のKinasesへの影響を低減することは困難であった。c-Met Allosteric部位を標的とした本研究は、極めて新規性及び独創性に富んでおり、学術的にも社会的にも重要な意義を持つと考えられる。