title: Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.
abstract: On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Xixiang
authors.initials: X
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Biophysics and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China.
authors.forename: Xiao-E
authors.initials: XE
authors.lastname: Yan
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biophysics and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biophysics and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China.
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Jing
authors.identifier: 0000-0001-9513-3591
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Qingsong
authors.identifier: 0000-0002-7829-2547
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017354:Point Mutation; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors