Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

Small-molecule fibroblast growth factor receptor (FGFR)
inhibitors
have emerged as a promising antitumor therapy. Herein, by further
optimizing the lead compound 1 under the guidance of
molecular docking, we obtained a series of novel covalent FGFR inhibitors.
After careful structure–activity relationship analysis, several
compounds were identified to exhibit strong FGFR inhibitory activity
and relatively better physicochemical and pharmacokinetic properties
compared with those of 1. Among them, 2e potently and selectively inhibited the kinase activity of FGFR1–3
wildtype and high-incidence FGFR2-N549H/K-resistant mutant kinase.
Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable
antiproliferative activity in FGFR-aberrant cancer cell lines. In
addition, the oral administration of 2e in the FGFR1-amplified
H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models
demonstrated potent antitumor efficacy, inducing tumor stasis or even
tumor regression.