Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Significance Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for the treatment of various cancers. All currently approved kinase inhibitors eventually are rendered useless by the emergence of drug-resistant tumors. We used structure-based drug design to develop the first, to our knowledge, selective, next-generation covalent FGFR inhibitors that can overcome the most common form of kinase inhibitor resistance, the mutation of the so-called “gatekeeper” residue located in the ATP-binding pocket. We also describe a novel kinase inhibitor design strategy that uses a single electrophile to target covalently cysteines that are located in different positions within the ATP-binding pocket. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance.