title: Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine⁷⁹⁰ → methionine⁷⁹⁰ mutant.
abstract: The EGFR(T790M) mutant contributes approximately 50% to clinically acquired resistance against gefitinib or erlotinib. However, almost all the single agent clinical trials of the second generation irreversible EGFR inhibitors appear inadequate to overcome the EGFR(T790M)-related resistance. We have designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors. The most potent compounds, 2q and 2s, inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC(50) values in subnanomolar ranges, including the T790M mutants. The kinase inhibitory efficiencies of the compounds were further validated by Western blot analysis of the activation of EGFR and downstream signaling in cancer cells harboring different mutants of EGFR. The compounds also strongly inhibited the proliferation of H1975 non small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to normal cells. Moreover, 2s displayed promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model.
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.forename: Lianwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Shilin
authors.initials: S
authors.lastname: Xu
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Xu
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008968:Molecular Conformation; D009154:Mutation; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013912:Threonine / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011799:Quinazolines; D013912:Threonine; D008715:Methionine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib