中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
热门
Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl5-(3,4,5-trimethoxybenzamido)phenyI)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor

文献类型:期刊论文

AuthorLiang, Xiaofei1,2; Lv, Fengchao1,3; Wang, Beilei1,3; Yu, Kailin1,3; Wu, Hong1,2; Qi, Ziping1,2; Jiang, Zongru1,3; Chen, Cheng1,3; Wang, Aoli1,3; Miao, Weili4
SourceJOURNAL OF MEDICINAL CHEMISTRY
Issued Date2017-03-09
Volume60Issue:5Pages:1793-1816
DOI10.1021/acsjmedchem.6b01413
SubtypeArticle
English AbstractBMX 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.
WOS KeywordGROWTH-FACTOR RECEPTOR ; TYROSINE KINASE ; COVALENT ; ETK/BMX ; FAMILY ; CELLS ; GENE ; BTK ; ACTIVATION ; EXPRESSION
WOS Research AreaPharmacology & Pharmacy
Language英语
WOS IDWOS:000396296100013
Funding OrganizationNational 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 Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "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 ; 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 ; 81402797 ; 81402797 ; 81402797 ; 81402797 ; 81603123) ; 81603123) ; 81603123) ; 81603123) ; 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 Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; National Key Research and Development Program of China(National Key Research and Development Program of China (no. 2016YFA0400900) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Postdoctoral Innovative Talent Support Program(BX201600169) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; Natural Science Foundation of Anhui province(1608085QH180) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" of Chinese Academy of Sciences (CAS) ; "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 ; 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 ; 81402797 ; 81402797 ; 81402797 ; 81402797 ; 81603123) ; 81603123) ; 81603123) ; 81603123)