The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM. Additionally, these pyrimidine derivatives also exhibited enhanced activity to block the proliferation of B-cell lymphoma cells compared with the representative BTK inhibitor ibrutinib. In particular, two structure-specific compounds 7b and 7e displayed stronger activity than reference agents in cell-based evaluation, with IC₅₀ values lower than 10 μM. Further biological studies, including flow cytometric analysis, and a xenograft model for in vivo evaluation, also indicated their efficacy and low toxicity in the treatment of B-cell lymphoma. These findings provide a new insight for the development of novel anti-B-cell lymphoma drugs with multi-target actions.

BTK和JAK3受体酪氨酸激酶是治疗B细胞淋巴瘤的两个有效靶点。在这里，我们报告鉴定几类嘧啶衍生物作为有效的BTK和JAK3双重抑制剂。在这些分子中，大约三分之二的化合物在浓度低于10 nM时显示出强大的抑制能力，还有四种化合物（7e，7g，7m和7n浓度低于1 nM时，可显着抑制BTK和JAK3酶的磷酸化。另外，与代表性的BTK抑制剂依鲁替尼相比，这些嘧啶衍生物还表现出增强的活性以阻断B细胞淋巴瘤细胞的增殖。特别地，在基于细胞的评估中，两种结构特异性化合物7b和7e表现出比参比剂更强的活性，且IC ₅₀值低于10μM。进一步的生物学研究，包括流式细胞术分析和体内异种移植模型评估也表明了它们在治疗B细胞淋巴瘤方面的功效和低毒性。这些发现为开发具有多靶点作用的新型抗B细胞淋巴瘤药物提供了新的见识。