Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors.

Yingxue Li, Yaoyao Chang, Jianfang Fu, Rongcai Ding, Lingyun Zhang, Tian Liang, Yajing Liu, Yue Liu, Jinxing Hu

European journal of medicinal chemistry 2021 Dec 15

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To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFRT790M) for use as EGFRL858R/T790M kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFRL858R/T790M, with an IC50 value of 4.0 nM and more than 42-fold selectivity for EGFRWT (IC50 = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC50 value of 0.086 μΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFRL858R/T790M. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Citation

Yingxue Li, Yaoyao Chang, Jianfang Fu, Rongcai Ding, Lingyun Zhang, Tian Liang, Yajing Liu, Yue Liu, Jinxing Hu. Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors. European journal of medicinal chemistry. 2021 Dec 15;226:113845