Key Laboratory of Chemical Genomics, Key Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University , Shenzhen, 518055, China.
J Med Chem. 2014 Jun 26;57(12):5112-28. doi: 10.1021/jm4017762. Epub 2014 Jun 10.
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.
布鲁顿酪氨酸激酶（Btk）是治疗多种 B 细胞谱系癌症的有吸引力的药物靶点。伊布替尼是一种首创的共价不可逆 Btk 抑制剂，在多项临床试验中显示出了令人印象深刻的效果。在此，我们提出了一系列新型的 2,5-二氨基嘧啶共价不可逆 Btk 抑制剂。与伊布替尼相比，这些抑制剂对分析的激酶表现出不同的选择性特征，以及对 Btk 的激活和催化活性的双重抑制作用模式，从而抵消了 Btk 的负调节环。该系列中的两个化合物，31 和 38，对多种 B 细胞淋巴瘤细胞系表现出很强的抗增殖活性，包括生发中心 B 细胞样弥漫性大 B 细胞淋巴瘤（GCB-DLBCL）细胞。此外，化合物 31 显著抑制了小鼠异种移植模型中的肿瘤生长。
