Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC 50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1 , FGFR3 , and FGFR4 , respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC 50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents. • 34 new FGFR2 inhibitors were designed, synthesized and evaluated. • LHQ490 selectively inhibited FGFR2 kinase activity with an IC 50 of 5.2 nM. • LHQ490 selectively suppressed the proliferation of FGFR2-driven cancer cells.