Design, synthesis, and biological evaluation of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines as potent EGFRT790M/L858R inhibitors to treat non-small cell lung cancer

• Published in: Bioorganic & medicinal chemistry 2022-11, Vol.74, p.117052-117052, Article 117052
• Main Authors: Tian, Liangliang, Li, Xing, Lv, Zhenying, Yang, Yin, Wang, Luhong, Xu, Dawei, Ma, Xiaodong, Xu, Youjun
• Format: Article
• Language: English
• Subjects: 2-arylaminopyrimidines; EGFRT790M/L858R; Inhibitors; Non-small cell lung cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.117052

[Display omitted] •Novel 2-arylamino-4-(piperidin-4-yloxy)pyrimidines as potent EGFRT790M/L858R inhibitors.•9i displayed strong inhibitory potency against EGFRT790M/L858R kinase and H1975 cell proliferation.•9i demonstrated highly selective inhibitory effects toward EGFRT790M/L858R over EGFRWT.•9i possessed low cytotoxicity against normal human bronchial epithelia (HBE) and L-02 cells. Three types of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines (I–III) were designed and synthesized as covalent EGFR(epidermal growth factor receptor)T790M/L858R inhibitors by replacement of the common reported 4-(3-amino)phenoxyl moiety with 4-(4-hydroxy)piperidine-4-oxyl, and the introduction of fused-thiophene or -pyrrole on the pyrimidine core to strategically achieve conformational restriction. According to our biological evaluation, it was found that compound 9i could potently suppress EGFRT790M/L858R kinase and H1975 cell proliferation, with IC50 values of 4.902 nM and 0.6210 μM, respectively. Further study showed that 9i not only demonstrated highly selective inhibitory effects toward EGFRT790M/L858R over wild-type EGFR (EGFRWT), but it also had low cytotoxicity against normal HBE(human bronchial epithelial) and L-02 cells. Action mechanism studies showed that 9i effectively hindered cell migration and promoted apoptosis by AO(Acridine Orange)/EB(Ethidium Bromide) staining. These data would provide important clues for the screening of novel covalent EGFRT790M/L858R inhibitors for non-small cell lung cancer (NSCLC) treatment.