Discovery of Novel Bruton’s Tyrosine Kinase (BTK) Inhibitors Bearing a N,9-Diphenyl-9H-purin-2-amine Scaffold

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• 作者：Yang Ge ; Yue Jin ; Changyuan Wang ; Jianbin Zhang ; Zeyao Tang ; Jinyong Peng ; Kexin Liu ; Yanxia Li ; Youwen Zhou ; Xiaodong Ma
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1050-1055
• 全文大小：501K
• ISSN：1948-5875

文摘

Based on the pyrimidine skeleton of EGFR^T790M inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC₅₀ values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 μM. The activity of the subject compound as determined by the CCK-8 method and apoptosis analysis validated that inhibitor 10j is slightly more potent than AVL-292 and ibrutinib. The results of these experimental explorations suggested that 10j could serve as a valuable molecule for control of leukemia pending further developments