Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3

Upregulation of the fibroblast growth factor receptor
(FGFR) signaling
pathway has been implicated in multiple cancer types, including cholangiocarcinoma
and bladder cancer. Consequently, small molecule inhibition of FGFR
has emerged as a promising therapy for patients suffering from these
diseases. First-generation pan-FGFR inhibitors, while highly effective,
suffer from several drawbacks. These include treatment-related hyperphosphatemia
and significant loss of potency for the mutant kinases. Herein, we
present the discovery and optimization of novel FGFR2/3 inhibitors
that largely maintain potency for the common gatekeeper mutants and
have excellent selectivity over FGFR1. A combination of meticulous
structure–activity relationship (SAR) analysis, structure-based
drug design, and medicinal chemistry rationale ultimately led to compound 29, a potent and selective FGFR2/3 inhibitor with excellent in vitro absorption, distribution, metabolism, excretion
(ADME), and pharmacokinetics in rat. A pharmacodynamic study of a
closely related compound established that maximum inhibition of downstream
ERK phosphorylation could be achieved with no significant effect on
serum phosphate levels relative to vehicle.