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

In this month’s featured publication, researchers in Dr. Gray’s group expand upon previous studies of the FGFR receptor, a protein found mutated in a subset of pilocytic astrocytomas.  However, a common problem in cancer is development of tumor resistance to chemotherapy over time.  Using structure-based drug design, they developed two next-generation covalent inhibitors that can overcome the most common form of resistance, a mutation of the FGFR itself, called the gate-keeeper mutation.  These new inhibitors prevented the actions of FGFR on cultured cells, and will serve as prototype inhibitors that will undergo further preclinical validation.