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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
Liang, 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; Wang, Wenchao1,2; Hu, Zhenquan1,2; Liu, Juan1,3; Liu, Xiaochuan1,2; Zhao, Zheng1,2; Wang, Li1,3; Zhang, Shanchuan2,5; Ye, Zi6; Wang, Chu6; Ren, Tao7; Wang, Yinsheng4; Liu, Qingsong1,2,3,7; Liu, Jing1,2
2017-03-09
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
Volume60Issue:5Pages:1793-1816
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.
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
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)
DOI10.1021/acsjmedchem.6b01413
WOS KeywordGROWTH-FACTOR RECEPTOR ; TYROSINE KINASE ; COVALENT ; ETK/BMX ; FAMILY ; CELLS ; GENE ; BTK ; ACTIVATION ; EXPRESSION
Indexed BySCI
Language英语
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)
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000396296100013
Citation statistics
Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/32871
Collection中科院强磁场科学中心
Affiliation1.Chinese Acad Sci, High Magnet Field Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
2.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
3.Univ Sci & Technol China Riverside, Hefei 230036, Anhui, Peoples R China
4.Univ Calif Riverside, Dept Chem, 900 Univ Ave, Riverside, CA 92521 USA
5.Hefei Cosource Med Technol Co Ltd, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
6.Peking Univ, Synthet & Funct Biomol Ctr,Peking Tsinghua Ctr Li, Beijing Natl Lab Mol Sci,Coll Chem & Mol Engn, Key Lab Bioorgan Chem & Mol Engn,Minist Educ, Beijing 100871, Peoples R China
7.Chinese Acad Sci, Hefei Inst Phys Sci, Precis Targeted Therapy Discovery Ctr, Inst Technol Innovat, Hefei 230088, Anhui, Peoples R China
Recommended Citation
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-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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(5):1793-1816.
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-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.JOURNAL OF MEDICINAL CHEMISTRY,60(5),1793-1816.
MLA Liang, Xiaofei,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 60.5(2017):1793-1816.
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