title: Design, synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors.
abstract: A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC50) values of 17 compounds against EGFR wt were less than 0.020μM, and those of 12 compounds were less than 0.010μM. The IC50 values of 10 compounds against EGFR T790M/L858R were less than 0.005μM. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1μM. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1μM), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Ji
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Peng
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China. Electronic address: hxie@simm.ac.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Electronic address: hliu@mail.shcnc.ac.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR T790M/L858R; Irreversible EGFR inhibitor; Thieno[2,3-d]pyrimidines