Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds12and17emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds12and17displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound17retained cells in the G2/M phase and induced apoptosis. Compounds12and17could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.
多项研究报道，Dyrk1A、Dyrk1B和Clk1在多种癌症中过度表达，提示其在恶性疾病中发挥作用。本文介绍了一类靶向Dyrk1A、Dyrk1B和Clk1的新型选择性激酶抑制剂。该成果通过改造我们前期基于5-甲氧基苯并噻吩-2-甲酰胺骨架的选择性Clk1抑制剂实现。通过引入5-羟基基团，我们增强了其形成额外氢键相互作用的能力，从而将抑制效应拓展至Dyrk1A和Dyrk1B激酶。在该系列化合物中，化合物12和17显示出对Dyrk1A、Dyrk1B和Clk1最强的多激酶抑制活性。进一步评估显示，这两种先导化合物对同样参与癌症发生的密切关联激酶Haspin和Clk2也具有抑制活性。化合物12和17在多种癌细胞系中表现出高效力，且对非肿瘤细胞影响极小。通过检测这些抑制剂对细胞周期分布的影响，发现化合物17能将细胞阻滞在G2/M期并诱导细胞凋亡。化合物12和17还能提高cleaved caspase-3和Bax蛋白水平，同时降低抗凋亡蛋白Bcl-2的表达。这些发现支持将这些化合物作为新型抗癌药物进行进一步研究开发。
肿瘤(癌症)患者之家