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

Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-05, Vol.131, p.107-125
Main Authors: Liang, Qianmao, Chen, Yongfei, Yu, Kailin, Chen, Cheng, Zhang, Shouxiang, Wang, Aoli, Wang, Wei, Wu, Hong, Liu, Xiaochuan, Wang, Beilei, Wang, Li, Hu, Zhenquan, Wang, Wenchao, Ren, Tao, Zhang, Shanchun, Liu, Qingsong, Yun, Cai-Hong, Liu, Jing
Format: Article
Language:English
Subjects:
B-cell lymphoma
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacology
BTK
Cells, Cultured
Dose-Response Relationship, Drug
Drug Discovery
Humans
Irreversible inhibitor
Kinase inhibitor
Molecular Structure
Morpholines - chemical synthesis
Morpholines - chemistry
Morpholines - pharmacology
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - metabolism
Structure-Activity Relationship
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Summary:Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases 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 μM. 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:
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.03.001