Glycogen synthase kinase 3β (GSK-3β) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC₅₀ values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3β. Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3β is mediated by the ubiquitin-proteasome system (UPS). In addition, PG21 protects against glutamate-induced cell death in HT-22 cells. As the first PROTAC example to degrade GSK-3β protein, the present study has provided potential candidates for further investigation in the biological function of GSK-3β protein and its association with diseases.

糖原合酶激酶3β（GSK-3β）涉及多种疾病，例如神经退行性疾病，躁郁症和糖尿病。在这项研究中，基于E3泛素连接酶大脑（CRBN）设计并合成了一系列针对嵌合体的异双功能小分子蛋白水解（PROTAC）。大多数PROTAC表现出良好的抑制活性，IC ₅₀值达到两位数纳摩尔水平，对GSK-3β的蛋白降解能力中等。Western印迹数据表明，化合物PG21可以剂量依赖性方式有效降解GSK-3β，在2.8μM时可诱导44.2％的蛋白质降解。进一步的药理实验表明PG21的能力GSK-3β的降解由泛素-蛋白酶体系统（UPS）介导。此外，PG21还可以防止谷氨酸诱导的HT-22细胞死亡。作为第一个降解GSK-3β蛋白的PROTAC实例，本研究为进一步研究GSK-3β蛋白的生物学功能及其与疾病的关系提供了潜在的候选对象。