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 | |
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 |
2017-05-05 | |
卷号 | 131页码:107-125 |
关键词 | Btk Irreversible Inhibitor Kinase Inhibitor Structure-activity Relationship B-cell Lymphoma |
DOI | 10.1016/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) ; 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内容类型 | 期刊论文 |
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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