Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
Marine Biomedical Research Institute of Qingdao, Qingdao, 266237, China.
Eur J Med Chem. 2024 Dec 5;279:116883. doi: 10.1016/j.ejmech.2024.116883. Epub 2024 Sep 14.
Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC of 2.58 μM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.
先天免疫分子 STING 的异常激活可引发炎症和自身免疫性疾病。针对 STING 的小分子抑制剂已被证明对这些疾病具有治疗效果。此外，利用降解剂来靶向 STING 是一种新的药物设计策略。因此，我们设计并合成了一系列针对 STING 的共价降解剂。其中，化合物 P8 表现出最高的降解能力，在 THP-1 细胞中 24 小时的 DC 为 2.58 μM。在 THP-1 细胞中，P8 通过溶酶体途径特异性降解 STING 蛋白，作为双重降解剂和抑制剂发挥抗炎作用。相反，在 RAW264.7 细胞中，P8 仅作为抑制剂发挥作用，而对 STING 蛋白水平没有降解能力。此外，P8 在顺铂诱导的急性肾损伤模型中表现出肾脏保护作用。这些结果突出了进一步研究化合物 P8 的重要潜力。
