title: Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.
abstract: EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR(WT). Finally, the most representative compound 17d was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR(L858R/T790M) over EGFR(WT), which may play an important role in designing new classes of mutant-selective EGFR inhibitors.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Yongjia
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Deheng
authors.initials: D
authors.lastname: Sun
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Zhenjiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, 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, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology , Shanghai, 200237, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011621:Pteridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C000620112:6,7-dioxo-6,7-dihydropteridine; D047428:Protein Kinase Inhibitors; D011621:Pteridines; C512478:EGFR protein, human; D066246:ErbB Receptors