刺
干扰素基因刺激剂
蛋白质水解
化学
体内
干扰素
药理学
免疫学
受体
生物
先天免疫系统
生物化学
酶
遗传学
工程类
航空航天工程
作者
Lixin Jin,Lin Yuan,Yong Ruan,Bulian Deng,Zicao Yang,Yichang Ren,Ling Li,Ting Liu,Hai Zhao,Ruiyao Mai,Jianjun Chen
标识
DOI:10.1021/acs.jmedchem.1c01948
摘要
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 (C-170) and pomalidomide (a CRBN ligand). These compounds demonstrated moderate STING-degrading activities. Among them, SP23 achieved the highest degradation potency with a DC50 of 3.2 μM. Importantly, SP23 exerted high anti-inflammatory efficacy in a cisplatin-induced acute kidney injury mouse model by modulating the STING signaling pathway. Taken together, SP23 represents the first PROTAC degrader of STING deserving further investigation as a new anti-inflammatory agent.
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