As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via “click reaction” to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments.

酪蛋白激酶2（CK2）作为一种普遍存在的，高度多效且具有组成型活性的丝氨酸/苏氨酸蛋白激酶，由于其在癌细胞中的过表达而与肿瘤发生密切相关。在这里，我们通过“点击反应”报告了几种针对嵌合体（PROTACs）的蛋白水解作用，以连接CK2抑制剂（CX-4945）和pomalidomide降解CK2蛋白。其中，化合物2以剂量和时间依赖性方式降解CK2，并通过募集泛素-蛋白酶体系统将CK2保持在较低的基础水平。CK2的降解导致Akt的磷酸化减少和p53的上调。作为CK2蛋白降解物，2 帕金森氏病对CX-4945具有类似的细胞毒性，但其作用机理与CK2抑制剂完全不同，这表明PROTAC降解CK2蛋白是癌症治疗的一种潜在方法。