Identification of Piperazinyl–Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation

The
fibroblast growth factor receptor (FGFR) signaling pathway
plays important roles in cellular processes such as proliferation,
differentiation, and migration. In this study, we highlighted the
potential of FGFR inhibitors bearing the (S)-3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene scaffold containing a crucial 3-pyridyl group for
the treatment of FGFR mutant cancers. The representative compound
(S)-23, which was identified
through comprehensive evaluation, exhibited potent antiproliferative
activity with GI50 in the range of 6.4–10.4 nM against
FGFR1 fusion protein-carrying, FGFR2-amplified, and FGFR2 mutant cancer
cell lines and good antiproliferative activity against FGFR3 translocation
and mutant FGFR4 cancer cell lines, as well as potency assessment
against FGFR1–4 kinases. Moreover, compound (S)-23 exhibited favorable pharmacokinetic
properties, low potential for drug–drug interactions, and very
potent antitumor activity in MFE-296 xenograft mouse models with a
TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that
compound (S)-23 is a potential
therapeutic agent for FGFR mutant tumors.