Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: Xiao, Qiang; Qu, Rong; Gao, Dingding; Yan, Qi; Tong, Linjiang; Zhang, Wei; Ding, Jian; Xie, Hua; Li, Yingxia
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 12(2016)
• Page Start: 2673
• Page End: 2680
• Publication Date: 2016-06-15
• Subjects: YXBJKXUKIDUKIH-UHFFFAOYSA-N -- BULITYBNVIHSDM-UHFFFAOYSA-N -- YDWRFDRHSNTINI-UHFFFAOYSA-N -- JGVSJOHBWPEWKW-UHFFFAOYSA-N -- XJCBAYFIITUVDS-UHFFFAOYSA-N -- WAZLQAVHYOQHHY-UHFFFAOYSA-N -- UUAOWKSAEYOOIY-UHFFFAOYSA-N -- UGWGOOAEFJICES-UHFFFAOYSA-N -- MTXGVGJDJNQPCL-UHFFFAOYSA-N -- LYCJWVRLAGIQEB-UHFFFAOYSA-N; 5-(Methylthio)pyrimidine derivatives -- Mutant selective inhibitors -- Epidermal growth factor inhibitor -- NSCLC -- Structure-based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.032
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: To overcome the drug-resistance of first generation EGFR inhibitors and the nonselective toxicities of second generation inhibitors among NSCLC patients, a series of 5-(methylthio)pyrimidine derivatives were discovered as novel EGFR inhibitors, which harbored not only potent enzymatic and antiproliferative activities against EGFR L858R/T790M mutants, but good selectivity over wide-type form of the receptor. This goal was achieved by employing structure-based drug design and traditional optimization strategies, based on WZ4002 and CO1686. These derivatives inhibited the enzymatic activity of EGFR L858R/T790M mutants with IC50 values in subnanomolar ranges, while exhibiting hundreds of fold less potency on EGFR WT . These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFR L858R/T790M, while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFR WT . The EGFR kinase inhibitory and antiproliferative activities were further validated by Western blot analysis for activation of EGFR and the downstream signaling in cancer cells.