Download MendeleyStructure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase.
Yen-Pon, E., Li, B., Acebron-Garcia-de-Eulate, M., Tomkiewicz-Raulet, C., Dawson, J., Lietha, D., Frame, M.C., Coumoul, X., Garbay, C., Etheve-Quelquejeu, M., Chen, H.(2018) ACS Chem Biol 13: 2067-2073
- PubMed: 29897729
- DOI: https://doi.org/10.1021/acschembio.8b00250
- Primary Citation of Related Structures:
6GCR, 6GCW, 6GCX - PubMed Abstract:
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.
Organizational Affiliation:
Chemistry of RNA, Nucleosides, Peptides and Heterocycles, CNRS UMR8601 , Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale , 45 rue des Saints-Pères , 75270 Paris Cedex 06 , France.
