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

作者：Li, Xitao; Zuo, Yingying; Tang, Guanghui; Wang, Yan; Zhou, Yiqing; Wang, Xueying; Guo, Tianlin; Xia, Mengying; Ding, Ning; Pan, Zhengying^*

来源：Journal of Medicinal Chemistry, 2014, 57(12): 5112-5128.

DOI：10.1021/jm4017762

• GROWTH-FACTOR RECEPTOR
• B-CELL-RECEPTOR
• SELECTIVE INHIBITORS
• RATIONAL DESIGN
• BTK INHIBITOR
• POTENT
• ACTIVATION
• ARTHRITIS
• BCR
• MECHANISMS

Bruton's 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.

• 出版日期2014-6-26
• 单位北京大学; 北京市肿瘤防治研究所