2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors

Structural optimization of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives yielded new selective FGFR inhibitors. Compound 2l covalently inhibited FGFR1-3 kinase with IC50 values of 1.06, 0.84 and 5.38 nM, respectively. Compound 2l significantly suppressed the growth of FGFR-amplified cancer cell lines and was less potent against FGFR-negative cancer cell lines and human normal liver HL7702 cells. Western blot analysis revealed that 2l dose-dependently inhibited the phosphorylation of FGFR in SUM52 cells bearing amplified-FGFR2 at nanomolar concentrations.118