Discovery of   2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxyben   zamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078)   as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase   in the X Chro

doi:10.1021/acsjmedchem.6b01413

CORC > 北京大学 > 化学与分子工程学院

	Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxyben zamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chro
	Liang, Xiaofei ; Lv, Fengchao ; Wang, Beilei ; Yu, Kailin ; Wu, Hong ; Qi, Ziping ; Jiang, Zongru ; Chen, Cheng ; Wang, Aoli ; Miao, Weili ; Wang, Wenchao ; Hu, Zhenquan ; Liu, Juan ; Liu, Xiaochuan ; Zhao, Zheng ; Wang, Li ; Zhang, Shanchuan ; Ye, Zi ; Wang, Chu ; Ren, Tao ; Wang, Yinsheng ; Liu, Qingsong ; Liu, Jing
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017
关键词	GROWTH-FACTOR RECEPTOR TYROSINE KINASE COVALENT ETK/BMX FAMILY CELLS GENE BTK ACTIVATION EXPRESSION
DOI	10.1021/acsjmedchem.6b01413
英文摘要	BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase. Given the fact that BMX mediated signaling pathway is still not fully understood, compound 41 would serve as a useful pharmacological tool to elucidate the detailed mechanism of BMX mediated signaling pathways.; National Natural Science Foundation of China [U1432250, 81402797, 81603123]; National Key Research and Development Program of China [National Key Research and Development Program of China (no. 2016YFA0400900]; Postdoctoral Innovative Talent Support Program [BX201600169]; Natural Science Foundation of Anhui province [1608085QH180]; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS); CAS/SAFEA International Partnership Program for Creative Research Teams; SCI(E); ARTICLE; 5; 1793-1816; 60
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/474633]
专题	化学与分子工程学院
推荐引用方式 GB/T 7714	Liang, Xiaofei,Lv, Fengchao,Wang, Beilei,et al. Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxyben zamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chro[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017.
APA	Liang, Xiaofei.,Lv, Fengchao.,Wang, Beilei.,Yu, Kailin.,Wu, Hong.,...&Liu, Jing.(2017).Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxyben zamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chro.JOURNAL OF MEDICINAL CHEMISTRY.
MLA	Liang, Xiaofei,et al."Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxyben zamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chro".JOURNAL OF MEDICINAL CHEMISTRY (2017).