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
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
复制标题
N-(3-(5-((3-丙烯酰氨基-4-(吗啉-4-羰基)苯基)氨基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-2的发现
DOI：
10.1016/j.ejmech.2017.03.001
复制
发表时间：
2017-05-05
影响因子：
6.7
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liang, Qianmao;Chen, Yongfei;Liu, Jing
目前有几种靶向Cys 481残基的不可逆BTK抑制剂正在临床前或临床开发中。然而，这些抑制剂中的大多数也靶向其他Idnases，如BMX，JAK 3和EGFR，它们具有高度相似的活性半胱氨酸残基。通过基于结构的药物设计方法，我们发现了一种高效（IC 50：7 nM）不可逆BTK抑制剂化合物9（CHMFL-BTK-01），其在1 μ M浓度下在468种激酶/突变体中在KINOMEscan中显示出高选择性特征（S评分（35）= 0.00）。化合物9完全阻断BMX、JAK 3和EGFR的活性。X射线晶体结构和半胱氨酸-丝氨酸突变介导的拯救实验都证实了9的不可逆结合模式。9还有效地抑制BTK Y223自身磷酸化（EC 50：
Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other Idnases 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 mu M. 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: