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Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-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.

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 irrevers... Full description

Journal Title: Journal of medicinal chemistry March 9, 2017, Vol.60(5), pp.1793-1816
Main Author: Liang, Xiaofei
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-4804 ; DOI: 10.1021/acs.jmedchem.6b01413
Link: http://search.proquest.com/docview/1863719393/?pq-origsite=primo
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title: Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-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.
format: Article
creator:
  • 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
subjects:
  • Benzamides–Chemistry
  • Bone Marrow–Pharmacokinetics
  • Cell Line–Pharmacology
  • Chromatography, Liquid–Enzymology
  • Drug Discovery–Methods
  • Humans–Pharmacokinetics
  • Protein Kinase Inhibitors–Pharmacology
  • Protein-Tyrosine Kinases–Antagonists & Inhibitors
  • Pyrimidines–Chemistry
  • Spectrum Analysis–Pharmacokinetics
  • Spectrum Analysis–Pharmacology
  • Spectrum Analysis–Methods
  • 2-((3-Acrylamido-4-Methylphenyl)Amino)-N-(2-Methyl-5-(3,4,5-Trimethoxybenzamido)Phenyl)-4-(Methylamino)Pyrimidine-5-Carboxamide
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Bmx Protein, Human
  • Protein-Tyrosine Kinases
ispartof: Journal of medicinal chemistry, March 9, 2017, Vol.60(5), pp.1793-1816
description: 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 IC 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.
language: eng
source:
identifier: E-ISSN: 1520-4804 ; DOI: 10.1021/acs.jmedchem.6b01413
fulltext: fulltext
issn:
  • 15204804
  • 1520-4804
url: Link


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titleDiscovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-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.
creatorLiang, 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
contributorLiang, Xiaofei (correspondence author) ; Liang, Xiaofei (record owner)
ispartofJournal of medicinal chemistry, March 9, 2017, Vol.60(5), pp.1793-1816
identifierE-ISSN: 1520-4804 ; DOI: 10.1021/acs.jmedchem.6b01413
subjectBenzamides–Chemistry ; Bone Marrow–Pharmacokinetics ; Cell Line–Pharmacology ; Chromatography, Liquid–Enzymology ; Drug Discovery–Methods ; Humans–Pharmacokinetics ; Protein Kinase Inhibitors–Pharmacology ; Protein-Tyrosine Kinases–Antagonists & Inhibitors ; Pyrimidines–Chemistry ; Spectrum Analysis–Pharmacokinetics ; Spectrum Analysis–Pharmacology ; Spectrum Analysis–Methods ; 2-((3-Acrylamido-4-Methylphenyl)Amino)-N-(2-Methyl-5-(3,4,5-Trimethoxybenzamido)Phenyl)-4-(Methylamino)Pyrimidine-5-Carboxamide ; Benzamides ; Protein Kinase Inhibitors ; Pyrimidines ; Bmx Protein, Human ; Protein-Tyrosine Kinases
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descriptionBMX 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 IC 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.
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titleDiscovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-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.
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titleDiscovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-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.
authorLiang, 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
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