Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase

Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK Inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC₅₀ value of 35 nM and exhibited potent Anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC₅₀ values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G₂/M phase, inducing tumor cell Apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK.