title: C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFRT790Mmutant.
abstract: With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFRT790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFRT790Minhibitors. Among them, the compound 10e displayed strong potency against the EGFRT790Menzyme, with the IC50of 11.0nM. Compound 10e also showed a higher SI value (SI=49.0) than rociletinib (SI=21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFRT790Mmutation, within the concentration of 2.91μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50=22.48μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFRT790Mover wild-type (EGFRWT).
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Anran
authors.initials: A
authors.lastname: Song
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: 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: Qiang
authors.initials: Q
authors.lastname: Meng
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: Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
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: D000814:Aniline Compounds / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; C023650:aniline
keywords: Diphenylpyrimidine; EGFR(T790M); Inhibitor; NSCLC; Resistance