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 <b>SI-24</b>, <b>SI-42</b>, and <b>SI-43</b> 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, <b>SI-43</b> promoted mutant-specific and proteasome-independent degradation of STING^S154 and STING^M155. Subcutaneous or oral administration of <b>SI-24</b>, <b>SI-42</b>, and <b>SI-43</b> 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.