Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor

Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angio-genesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multi-targeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (S AR) studies explored modifications to the thiazole, diazepinone, and aniline tail, which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.

Automated summary

The study introduced a novel series of small molecules targeting FAK with high potency and selectivity, among which lead compound BJG-03-025 showed promising biochemical FAK inhibition, kinase selectivity, and activity in cancer models. BJG-03-025 also demonstrated favorable pharmacokinetic properties in mice, making it a valuable chemical probe for evaluating FAK-dependent biology.