Discovery of Pyrrolopyrazine Carboxamide Derivatives as Potent and Selective FGFR2/3 Inhibitors that Overcome Mutant Resistance

Fibroblast growth factor receptors
(FGFRs) are established
oncogenic
drivers in various solid tumors. However, the approved FGFR inhibitors
face challenges with acquired resistance and dose-limiting adverse
effects associated with FGFR1/4 inhibition, limiting therapeutic efficacy.
Herein, we systematically explored linker and electrophile moieties
based on the pyrrolopyrazine carboxamide core and identified aniline
α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2 and FGFR3, even in the context
of common inhibitor-resistance mutations, including in the gatekeeper,
molecular brake, and activation loop regions. Compound 10 spared FGFR1/4 and other kinases without causing diarrhea and serum
phosphate elevation in vivo. Oral administration
of compound 10 induced tumor stasis or regression in
the SNU-16 gastric cancer model with favorable pharmacokinetics and
robust pharmacodynamic suppression.