Design of Potent Small-Molecule Stimulator of Interferon Gene Inhibitor and Stimulator of Interferon Gene Mutant-Specific Degrader.

Stimulator of interferon genes (STING) is involved in various autoimmune diseases. However, it is challenging to develop small-molecule STING inhibitors with potent activity. Herein, we designed a small-molecule STING inhibitor and STING mutant-specific degrader by binding two coupled pockets of a STING dimer. Structure optimization selected SI-24, SI-42, and SI-43 with low nanomolar activity to inhibit 2'3'-cyclic GMP-AMP (cGAMP)-induced STING activation and release of IFN-β and CXCL-10, which were far more potent than reported STING inhibitors. Moreover, the three lead compounds suppressed cGAMP-induced oligomerization of STING and phosphorylation of interferon regulatory factor 3 (IRF3) and STING. Surprisingly, SI-43 promoted mutant-specific and proteasome-independent degradation of STINGS154 and STINGM155. Subcutaneous or oral administration of SI-24, SI-42, and SI-43 reduced serum IFN-β and CXCL-10 in the cGAMP-induced autoimmune disease mouse model. Our dual-functional compounds provide a new strategy to investigate STING function through both inhibition and mutant-specific degradation in autoimmune diseases.