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Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor

文献类型：期刊论文

作者Liang, Qianmao1,2; Chen, Yongfei2,3; Yu, Kailin2,4; Chen, Cheng2,3; Zhang, Shouxiang5,6; Wang, Aoli2,4; Wang, Wei2,3; Wu, Hong2,4; Liu, Xiaochuan1,2; Wang, Beilei2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-05-05
卷号131页码:107-125
关键词Btk Irreversible Inhibitor Kinase Inhibitor Structure-activity Relationship B-cell Lymphoma
DOI10.1016/j.ejmech.2017.03.001
文献子类Article
英文摘要Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other Idnases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7 nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 mu M. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC50: <30 nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology. (C) 2017 Elsevier Masson SAS. All rights reserved.
WOS关键词X-LINKED AGAMMAGLOBULINEMIA ; B-CELL ; RHEUMATOID-ARTHRITIS ; ACTIVATION ; COVALENT ; IBRUTINIB ; POTENT ; GENE ; PROLIFERATION ; EXPRESSION
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000399266500008
资助机构Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; 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 ; 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 ; 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Hundred Talents Program of the Chinese Academy of Sciences ; Hundred Talents Program of the Chinese Academy of Sciences ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; Youth Foundation of National Natural Science Foundation of China(21402207) ; 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 ; 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 ; 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 ; 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 Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Basic Research Program (973) of China(2012CB917202) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; National Natural Science Foundation of China(31270769) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; Hefei Science Center CAS(2016HSCIU007) ; 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源URL[http://ir.hfcas.ac.cn:8080/handle/334002/33394]  
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.Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China
2.Chinese Acad Sci, High Field Magnet Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
3.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
4.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
5.Peking Univ, Hlth Sci Ctr, Inst Syst Biomed, Dept Biophys,Beijing Key Lab Tumor Syst Biol, Beijing 100191, Peoples R China
6.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China
7.Chinese Acad Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei Inst Phys Sci, Hefei 230088, Anhui, Peoples R China
8.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Qianmao,Chen, Yongfei,Yu, Kailin,et al. Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,131:107-125.
APA Liang, Qianmao.,Chen, Yongfei.,Yu, Kailin.,Chen, Cheng.,Zhang, Shouxiang.,...&Liu, Jing.(2017).Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,131,107-125.
MLA Liang, Qianmao,et al."Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 131(2017):107-125.

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来源：合肥物质科学研究院

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