Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China.
Eur J Med Chem. 2021 Jan 15;210:112949. doi: 10.1016/j.ejmech.2020.112949. Epub 2020 Oct 17.
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 IC 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）参与多种疾病，如神经退行性疾病、双相情感障碍和糖尿病。在这项研究中，基于 E3 泛素连接酶 cereblon（CRBN）设计并合成了一系列杂双功能小分子蛋白水解靶向嵌合体（PROTAC）。大多数 PROTAC 显示出良好的抑制活性，IC 值在十位数纳摩尔水平，对 GSK-3β 具有中等的蛋白降解能力。Western blot 数据显示，化合物 PG21 能够以剂量依赖的方式有效降解 GSK-3β，在 2.8 μM 时可诱导 44.2%的蛋白降解。进一步的药理学实验表明，PG21 降解 GSK-3β 的能力是由泛素-蛋白酶体系统（UPS）介导的。此外，PG21 可防止 HT-22 细胞中谷氨酸诱导的细胞死亡。作为首例降解 GSK-3β 蛋白的 PROTAC 示例，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药物。
