Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase

Expédite Yen-Pon (1, 2) , Bo Li (1, 2) , Marta Acebrón-Garcia-De-Eulate (3) , Céline Tomkiewicz-Raulet (4) , John Dawson (5) , Daniel Lietha (3) , Margaret C. Frame (5) , Xavier Coumoul (4) , Christiane Garbay (1, 2) , Mélanie Etheve-Quelquejeu (1, 2) , Huixiong Chen (1, 2)

1 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
2 UFR Biomédicale
3 Structural Biology Programme - Cell Signalling and Adhesion Group [Madrid, Spain]
4 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
5 Cancer Research UK Edinburgh Centre [Edinburgh, UK]

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.

Domaines: Chimie

Expédite Yen-Pon, Bo Li, Marta Acebrón-Garcia-De-Eulate, Céline Tomkiewicz-Raulet, John Dawson, et al.. Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase. ACS Chemical Biology, 2018, 13 (8), pp.2067-2073. ⟨10.1021/acschembio.8b00250⟩. ⟨hal-02196326⟩