Stimulator of interferon genes (STING), a homodimeric membrane receptor localized in the endoplasmic reticulum, plays a pivotal role in signaling innate immune responses. Inhibitors and proteolysis-targeting chimeras (PROTACs) targeting STING are promising compounds for addressing autoinflammatory and autoimmune disorders. In this study, we used a minimal covalent handle recently developed as the ligand portion of an E3 ligase. The engineered STING degrader with a low molecular weight compound covalently binds to STING and E3 ligase. Degrader showed sustained STING degradation activity at lower concentrations (3 µM, 48 h, about 75 % degradation) compared to a reported STING PROTAC, SP23. This discovery holds significance for its potential in treating autoinflammatory and autoimmune diseases, offering promising avenues for developing more efficacious STING-targeted therapies.

中文翻译：

---

双共价配体 STING 降解剂的开发

干扰素基因刺激物 (STING) 是一种位于内质网的同型二聚体膜受体，在先天免疫反应信号传导中发挥着关键作用。针对 STING 的抑制剂和蛋白水解靶向嵌合体 (PROTAC) 是治疗自身炎症和自身免疫性疾病的有前途的化合物。在这项研究中，我们使用了最近开发的最小共价手柄作为 E3 连接酶的配体部分。工程化的 STING 降解剂具有低分子量化合物，可与 STING 和 E3 连接酶共价结合。与报道的 STING PROTAC SP23 相比，Degrader 在较低浓度下表现出持续的 STING 降解活性（3 µM，48 小时，约 75% 降解）。这一发现对其治疗自身炎症和自身免疫性疾病的潜力具有重要意义，为开发更有效的 STING 靶向疗法提供了有希望的途径。