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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
Wang, Aoli1,2; Li, Xixiang1,3; Wu, Hong1,3; Zou, Fengming1,3; Yan, Xiao-E4,5; Chen, Cheng1,2; Hu, Chen1,2; Yu, Kailin1,2; Wang, Wenchao1,3; Zhao, Peng4,5; Wu, Jiaxin1,2; Qi, Ziping1,3; Wang, Wei1,3; Wang, Beilei1,2; Wang, Li1,2; Ren, Tao6; Zhang, Shanchun3,7; Yun, Cai-Hong4,5; Liu, Jing1,3; Liu, Qingsong1,2,3,6
2017-04-13
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
Volume60Issue:7Pages:2944-2962
AbstractOn 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.
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding OrganizationNational Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769)
DOI10.1021/acs.jmedchem.6b01907
WOS KeywordCELL LUNG-CANCER ; T790M MUTATION ; RESISTANCE ; SYSTEM ; CRYSTALLOGRAPHY ; GEFITINIB ; SOFTWARE ; BIOLOGY ; POTENT ; L858R
Indexed BySCI
Language英语
Funding OrganizationNational Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769)
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000399436100022
Citation statistics
Cited Times:11[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/33341
Collection中科院强磁场科学中心
Affiliation1.Chinese Acad Sci, High Magnet Field Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.CIIMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys, Beijing 100191, Peoples R China
5.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed, Beijing 100191, Peoples R China
6.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China
7.Hefei Cosource Med Technol Co Ltd, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
Recommended Citation
GB/T 7714
Wang, Aoli,Li, Xixiang,Wu, Hong,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(7):2944-2962.
APA Wang, Aoli.,Li, Xixiang.,Wu, Hong.,Zou, Fengming.,Yan, Xiao-E.,...&Liu, Qingsong.(2017).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.JOURNAL OF MEDICINAL CHEMISTRY,60(7),2944-2962.
MLA Wang, Aoli,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 60.7(2017):2944-2962.
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