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.
Keywords: 5-(Methylthio)pyrimidine derivatives; Epidermal growth factor inhibitor; Mutant selective inhibitors; NSCLC; Structure-based drug design.
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