Development of new dual inhibitors for c-Met targeting both allosteric and catalytic sites

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04315
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: National Defense Medical College
• Principal Investigator: Shinomiya Nariyoshi 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 分子生体制御学, 教授 (40505260)
• Co-Investigator(Kenkyū-buntansha): 田沼 靖一 東京理科大学, 薬学部薬学科, 教授 (10142449)
• Co-Investigator(Renkei-kenkyūsha): Xie Qian Quillen College of Medicine, East Tennessee State University, Department of Biomedical Sciences, Center of Excellence for Inflammation, Infectious Disease and Immunity ; Woude George F. Vande Van Andel Research Institute, Emeritus, Distinguished Scientific Fellow
• Research Collaborator: YOSHIMORI Atsushi 株式会社理論創薬研究所, 取締役社長 ; SAWASAKI Tatsuya 愛媛大学, プロテオサイエンスセンター, 教授 ; YUMOTO Fumiaki 高エネルギー加速研究機構, 特任准教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: c-Met / 受容体型チロシンキナーゼ / 分子創薬 / COSMOS法 / アロステリック効果 / デュアル・インヒビション

Outline of Final Research Achievements

We have developed new small molecules which target c-Met receptor type tyrosine kinase. In this study, we searched new compounds showing high affinity to c-Met kinase catalytic domain (ATP binding site), and performed the structural analysis of Vpep peptide that bound allosteric site of c-Met catalytic domain and suppressed its kinase activity. We also have strengthened the designing strategy of c-Met inhibitors and proceeded the creation of “dual inhibitors” by combining allosteric inhibitors (Ai) and catalytic inhibitors (Ci). Currently, we are further improving the design of drugs to develop final inhibitor molecules for c-Met.

Free Research Field

腫瘍生物学