Design of Potent Small-Molecule Stimulator of Interferon Gene Inhibitor and Stimulator of Interferon Gene Mutant-Specific Degrader
Hongyi Zhao, Luchen Zhang, Zhongwei Liu, Miao He, Meilin Wang, Qiuxia Li, Farzad Sarkari, Jinsong Tao, Bo Wen, Venkatesha Basrur, Hannah Myatt, Alexey I. Nesvizhskii, Duxin Sun
Abstract
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 STING S154 and STING M155 . 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.