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

Abstract

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.