Ge Yang, Wang Changyuan, Song Shijie, Huang Jiaxin, Liu Zhihao, Li Yongming, Meng Qiang, Zhang Jianbin, Yao Jihong, Liu Kexin, Ma Xiaodong, Sun Xiuli
Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China; College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, PR China.
College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, PR China.
Eur J Med Chem. 2018 Jan 1;143:1847-1857. doi: 10.1016/j.ejmech.2017.10.080. Epub 2017 Nov 14.
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 IC 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细胞淋巴瘤的两个经过验证且适合治疗的靶点。在此，我们报告了几类嘧啶衍生物作为强效BTK和JAK3双重抑制剂的鉴定结果。在这些分子中，约三分之二在浓度低于10 nM时表现出强大的抑制能力，四种化合物（7e、7g、7m和7n）在浓度低于1 nM时可显著抑制BTK和JAK3酶的磷酸化。此外，与代表性的BTK抑制剂依鲁替尼相比，这些嘧啶衍生物在阻断B细胞淋巴瘤细胞增殖方面也表现出增强的活性。特别是，两种结构特异性化合物7b和7e在基于细胞的评估中显示出比参考药物更强的活性，IC值低于10 μM。进一步的生物学研究，包括流式细胞术分析和用于体内评估的异种移植模型，也表明它们在治疗B细胞淋巴瘤方面具有疗效且毒性低。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解。
