European Journal of Medicinal Chemistry p. 1107 - 1117 (2017)
Update date:2022-07-30
Topics:
Yu, Lei
Huang, Minhao
Xu, Tianfeng
Tong, Linjiang
Yan, Xiao-e
Zhang, Zhang
Xu, Yong
Yun, Caihong
Xie, Hua
Ding, Ke
Lu, Xiaoyun
Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790Minhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790Mkinase and inhibited the proliferation of H1975?cells with IC50values 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 NCI[sbnd]H1975?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.
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