Discovery of a Series of 2,5-Diaminopyrimidine Covalent Irreversible Inhibitors of Bruton鈥檚 Tyrosine Kinase with in Vivo Antitumor Activity

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• 作者：Xitao Li ; Yingying Zuo ; Guanghui Tang ; Yan Wang ; Yiqing Zhou ; Xueying Wang ; Tianlin Guo ; Mengying Xia ; Ning Ding ; Zhengying Pan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5112-5128
• 全文大小：713K
• ISSN：1520-4804

文摘

Bruton鈥檚 tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors exhibited a different selectivity profile for the analyzed kinases as well as a dual-action mode of inhibition of both Btk activation and catalytic activity, which counteracts a negative regulation loop for Btk. Two compounds from this series, 31 and 38, showed potent antiproliferative activities toward multiple B-cell lymphoma cell lines, including germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound 31 significantly prevented tumor growth in a mouse xenograft model.