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Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation

文献类型：期刊论文

作者Wang, Aoli1,2; Yan, Xiao-E3,4; Wu, Hong1,2; Wang, Wenchao1,5; Hu, Chen1,2; Chen, Cheng1,2; Zhao, Zheng1,5; Zhao, Peng3,4; Li, Xixiang1; Wang, Li1,2
刊名ONCOTARGET
出版日期2016-10-25
卷号7期号:43页码:69760-69769
关键词Ibrutinib Egfr Kinase Dfg-in/c-helix-out Inactive Conformation Nsclc
DOI10.18632/oncotarget.11951
文献子类Article
英文摘要Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 mu M), Ibrutinib exhibited less efficient binding (Kd: 0.18 mu M). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix- out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC.
WOS关键词BRUTONS TYROSINE KINASE ; MANTLE-CELL LYMPHOMA ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; GROWTH-FACTOR RECEPTOR ; INHIBITORS ; BTK ; SYSTEM ; CRYSTALLOGRAPHY ; ACTIVATION ; RESISTANCE
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000387448300051
资助机构National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch 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 ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; 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 ; 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 Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; 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 ; National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch and Development Program of China(2016YFA0400900) ; National Key Reasearch 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 ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; NIH(P01 CA154303-03) ; 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 ; 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 Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; National Basic Research Program of China (973 Program)(2012CB917202) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; High-end User Cultivation Program of Hefei Science Center of CAS(2016HSC-IU007) ; 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
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/30181]  
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 Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Beijing Key Lab Tumor Syst Biol, Inst Syst Biomed,Dept Biophys, Beijing 100191, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China
5.Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China
6.Peking Univ, Peking Tsinghua Ctr Life Sci,Minist Educ, Coll Chem & Mol Engn,Key Lab Bioorgan Chem & Mol, Synthet & Funct Biomol Ctr,Beijing Natl Lab Mol S, Beijing 100871, Peoples R China
7.Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
8.Natl Inst Biol Sci, Collaborat Innovat Ctr Canc Med, Beijing 102206, Peoples R China
9.Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
10.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
推荐引用方式
GB/T 7714		 Wang, Aoli,Yan, Xiao-E,Wu, Hong,et al. Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation[J]. ONCOTARGET,2016,7(43):69760-69769.
APA Wang, Aoli.,Yan, Xiao-E.,Wu, Hong.,Wang, Wenchao.,Hu, Chen.,...&Liu, Qingsong.(2016).Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation.ONCOTARGET,7(43),69760-69769.
MLA Wang, Aoli,et al."Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation".ONCOTARGET 7.43(2016):69760-69769.

入库方式： OAI收割

来源：合肥物质科学研究院

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