Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors

• Published in: Bioorganic & medicinal chemistry 2016-06, Vol.24 (12), p.2673-2680
• Main Authors: Xiao, Qiang, Qu, Rong, Gao, Dingding, Yan, Qi, Tong, Linjiang, Zhang, Wei, Ding, Jian, Xie, Hua, Li, Yingxia
• Format: Article
• Language: English
• Subjects: 5-(Methylthio)pyrimidine derivatives; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Epidermal growth factor inhibitor; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Methylation; Molecular Docking Simulation; Mutant selective inhibitors; NSCLC; Point Mutation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Structure-based drug design
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.032

[Display omitted] 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 EGFRL858R/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 EGFRL858R/T790M mutants with IC50 values in subnanomolar ranges, while exhibiting hundreds of fold less potency on EGFRWT. These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFRL858R/T790M, while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFRWT. 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.