2 <i>H</i> -pyrazolo[3,4- <i>d</i> ]pyrimidin-4-amine derivatives as novel selective fibroblast growth factor receptor 2 (FGFR2) inhibitors

Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidin-4-amine derivative as novel, irreversible FGFR2 inhibitors. The optimal compound, <b>PLW559</b>, potently inhibited FGFR2 with an IC₅₀ value of 13.59 nM and demonstrated exceptional selectivity over FGFR1, FGFR3, and FGFR4. Covalent binding to the target was confirmed by mass spectrometry. In cellular models, <b>PLW559</b> exhibited potent and selective antiproliferative effects against FGFR2-driven cancer cells, effectively suppressed downstream FGFR2 signalling and induced cancer cell apoptosis. Notably, it showed minimal activity in non-FGFR2-dependent cells. This work presents a new class of selective FGFR2 inhibitors based on a novel scaffold, offering promising lead compounds for the development of FGFR2-target therapies.