焦点粘着
激酶
化学
表征(材料科学)
粘附
细胞生物学
生物化学
生物物理学
生物
纳米技术
信号转导
材料科学
有机化学
作者
Expédite Yen-Pon,Bo Li,Marta Acebrón-Garcia-de-Eulate,Céline Tomkiewicz-Raulet,John H. Dawson,Daniel Lietha,Margaret C. Frame,Xavier Coumoul,Christiane Garbay,Mélanie Etheve-Quelquejeu,Huixiong Chen
标识
DOI:10.1021/acschembio.8b00250
摘要
Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor.
科研通智能强力驱动
Strongly Powered by AbleSci AI