Fibroblast growth factor receptors
(FGFR) 2 and 3 have been established
as drivers of numerous types of cancer with multiple drugs approved
or entering late stage clinical trials. A limitation of current inhibitors
is vulnerability to gatekeeper resistance mutations. Using a combination
of targeted high-throughput screening and structure-based drug design,
we have developed a series of aminopyrazole based FGFR inhibitors
that covalently target a cysteine residue on the P-loop of the kinase.
The inhibitors show excellent activity against the wild-type and gatekeeper
mutant versions of the enzymes. Further optimization using SAR analysis
and structure-based drug design led to analogues with improved potency
and drug metabolism and pharmacokinetics properties.
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