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

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.