Structure-Based Design and Optimization of Novel, Potent and Selective Covalent FGFR2/3 Inhibitors with a Tricyclic Core.

ABSTRACT: Fibroblast growth factor receptors 2 and 3 (FGFR2/3) are attractive therapeutic targets in multiple human cancers. Here, we report the discovery of a series of tricyclic 1-(4-amino-5-ethynyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one derivatives as novel covalent FGFR2/3 inhibitors through structure-based design and optimization. The lead compound, KNT-0919, potently suppressed FGFR2- or FGFR3-driven Ba/F3 cells (IC₅₀ = 1.1 nM and 0.20 nM), with reduced activity against Ba/F3-FGFR1 cells (IC₅₀ = 17.1 nM) and parental Ba/F3 cells (IC₅₀ > 1000 nM). In a panel of 416 kinases, KNT-0919 selectively inhibited FGFR2/3 kinases, including clinically relevant mutants. Covalent modification of FGFR2/3 was

SUBMITTER: Lu X 

PROVIDER: S-EPMC13643868 | biostudies-literature | 2026 Jun

REPOSITORIES: biostudies-literature