title: Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors.
abstract: A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790Minhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858Rkinase (IC50=3.3nM), but also was able to repress the replication of H1975 cells harboring EGFRT790Mmutation at a concentration of 0.118μmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI=299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Song
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ge
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Zeyao
authors.initials: Z
authors.lastname: Tang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Respiratory Department, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China. Electronic address: liyanxia001@163.com.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
mesh_terms: D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001393:Azoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Azole-diphenylpyrimidine; EGFR T790M; Inhibitors; NSCLC; Synthesis