Liu Jin, Yuan Lin, Ruan Yong, Deng Bulian, Yang Zicao, Ren Yichang, Li Ling, Liu Ting, Zhao Huiting, Mai Ruiyao, Chen Jianjun
School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
J Med Chem. 2022 May 12;65(9):6593-6611. doi: 10.1021/acs.jmedchem.1c01948. Epub 2022 Apr 22.
The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (STING) pathway has been associated with the pathogenesis of many autoimmune and inflammatory disorders, and small molecules targeting STING have emerged as a new therapeutic strategy for the treatment of these diseases. While several STING inhibitors have been identified with potent anti-inflammatory effects, we would like to explore STING degraders based on the proteolysis-targeting chimera (PROTAC) technology as an alternative strategy to target the STING pathway. Thus, we designed and synthesized a series of STING protein degraders based on a small-molecule STING inhibitor () and pomalidomide (a CRBN ligand). These compounds demonstrated moderate STING-degrading activities. Among them, achieved the highest degradation potency with a DC of 3.2 μM. Importantly, exerted high anti-inflammatory efficacy in a cisplatin-induced acute kidney injury mouse model by modulating the STING signaling pathway. Taken together, represents the first PROTAC degrader of STING deserving further investigation as a new anti-inflammatory agent.
环磷酸鸟苷-腺苷合成酶-干扰素基因刺激因子（STING）通路的激活与许多自身免疫性和炎性疾病的发病机制相关，靶向STING的小分子已成为治疗这些疾病的一种新治疗策略。虽然已经鉴定出几种具有强效抗炎作用的STING抑制剂，但我们希望探索基于蛋白酶靶向嵌合体（PROTAC）技术的STING降解剂，作为靶向STING通路的替代策略。因此，我们基于小分子STING抑制剂（）和泊马度胺（一种CRBN配体）设计并合成了一系列STING蛋白降解剂。这些化合物表现出适度的STING降解活性。其中，在3.2 μM的DC下实现了最高的降解效力。重要的是，通过调节STING信号通路，在顺铂诱导的急性肾损伤小鼠模型中发挥了高抗炎功效。综上所述，作为一种新的抗炎剂，代表了首个值得进一步研究的STING的PROTAC降解剂。
