5GMP

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR T790M inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR L858R/T790M kinase and inhibited the proliferation of H1975?cells with IC 50 values of 2.0?nM and 40?nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975?cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.