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
文献类型：期刊论文
| 作者 | 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
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2017-04-13 |
| 卷号 | 60期号:7页码:2944-2962 |
| DOI | 10.1021/acs.jmedchem.6b01907 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | CELL LUNG-CANCER ; T790M MUTATION ; RESISTANCE ; SYSTEM ; CRYSTALLOGRAPHY ; GEFITINIB ; SOFTWARE ; BIOLOGY ; POTENT ; L858R |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000399436100022 |
| 资助机构 | 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) ; 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) |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/33341]  |
| 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, 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 |
| 推荐引用方式 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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来源：合肥物质科学研究院
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