title: Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors.
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.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qu
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Dingding
authors.initials: D
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D062105:Molecular Docking Simulation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: 5-(Methylthio)pyrimidine derivatives; Epidermal growth factor inhibitor; Mutant selective inhibitors; NSCLC; Structure-based drug design