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

ID: ALA5154887

Journal: J Med Chem

Title: Novel CRBN-Recruiting Proteolysis-Targeting Chimeras as Degraders of Stimulator of Interferon Genes with In Vivo Anti-Inflammatory Efficacy.

Authors: Liu J, Yuan L, Ruan Y, Deng B, Yang Z, Ren Y, Li L, Liu T, Zhao H, Mai R, Chen J.

Abstract: 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.

CiteXplore: 35452223

DOI: 10.1021/acs.jmedchem.1c01948

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