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Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode

文献类型：期刊论文

作者Hu, Chen1,2; Wang, Aoli1,2; Wu, Hong1,3; Qi, Ziping1,3; Li, Xixiang1,3; Yan, Xiao-E4; Chen, Cheng1,2; Yu, Kailin1,2; Zou, Fengming1,3; Wang, Wenchao1,3
刊名ONCOTARGET
出版日期2017
卷号8期号:11页码:18359-18372
关键词Egfr Egfrt790m Nsclc Kinase Inhibitors Drug Resistance
DOI10.18632/oncotarget.15443
文献子类Article
英文摘要EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct "DFG-in" and "cHelix-out" inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.
WOS关键词GROWTH-FACTOR RECEPTOR ; CELL LUNG-CANCER ; TYROSINE KINASE ; DRUG-RESISTANCE ; IN-VIVO ; ACTIVATION ; T790M ; COMPLEXES ; MECHANISM ; MUTATION
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000396877500080
资助机构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) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; 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 "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; 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 ; 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 ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; 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) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; 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 "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; 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 ; 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 ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; Postdoctoral Innovative Talents Support Program from China Postdoctoral Science Foundation(BX201600169) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769) ; National Science Foundation of China(31270769)
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/32872]  
专题合肥物质科学研究院_中科院强磁场科学中心
作者单位1.Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China
4.Peking Univ Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed, Beijing Key Lab Tumor Syst Biol & Ctr Mol & Trans, Beijing 100191, Peoples R China
5.Chinese Acad Sci, Hefei Inst Phys Sci, Precis Targeted Therapy Discovery Ctr, Inst Technol Innovat, Hefei 230088, Anhui, Peoples R China
6.Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Chen,Wang, Aoli,Wu, Hong,et al. Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode[J]. ONCOTARGET,2017,8(11):18359-18372.
APA Hu, Chen.,Wang, Aoli.,Wu, Hong.,Qi, Ziping.,Li, Xixiang.,...&Liu, Qingsong.(2017).Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode.ONCOTARGET,8(11),18359-18372.
MLA Hu, Chen,et al."Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode".ONCOTARGET 8.11(2017):18359-18372.

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来源：合肥物质科学研究院

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