Novel CRBN-Recruiting Proteolysis-Targeting Chimeras asDegraders of Stimulator of Interferon Genes with In Vivo Anti-Inflammatory Efficacy

作者：Liu, Jin; Yuan, Lin; Ruan, Yong; Deng, Bulian; Yang, Zicao; Ren, Yichang; Li, Ling; Liu, Ting; Zhao, Huiting; Mai, Ruiyao; Chen, Jianjun^*

来源：Journal of Medicinal Chemistry, 2022, 65(9): 6593-6611.

DOI：10.1021/acs.jmedchem.1c01948

• SMALL-MOLECULE PROTACS
• CYCLIC GMP-AMP
• PROTEIN-DEGRADATION
• DOCKING
• ACTIVATION
• PREDICTION
• INHIBITORS
• CHEMISTRY
• DISCOVERY
• COMPLEX

The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (STING) pathway has been associatedwith the pathogenesis of many autoimmune and inflammatorydisorders, and small molecules targeting STING have emerged as anew therapeutic strategy for the treatment of these diseases. Whileseveral STING inhibitors have been identified with potent anti-inflammatory effects, we would like to explore STING degradersbased on the proteolysis-targeting chimera (PROTAC) technology asan alternative strategy to target the STING pathway. Thus, wedesigned and synthesized a series of STING protein degraders basedon a small-molecule STING inhibitor (C-170) and pomalidomide (aCRBN ligand). These compounds demonstrated moderate STING-degrading activities. Among them,SP23achieved the highestdegradation potency with a DC50of 3.2 mu M. Importantly,SP23exerted high anti-inflammatory efficacy in a cisplatin-induced acute kidney injury mouse model by modulating the STING signalingpathway. Taken together,SP23represents thefirst PROTAC degrader of STING deserving further investigation as a new anti-inflammatory agent

• 单位
  南方医科大学