C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFRT790M mutant

Abstract

The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFR^T790M mutant. One of the most promising compounds, 9f, tightly binds to the EGFR^T790M mutant and strongly inhibits its enzymatic function with an IC₅₀ value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFR^T790M mutated H1975 NSCLC cells with an IC₅₀ value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.