Development and Characterization of a Noncovalent Stimulator of Interferon Genes Proteolysis-Targeting Chimeras

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway activates the immune response upon detection of cytosolic dsDNA and is a key regulator of innate immunity. Overactivation of cGAS-STING has been implicated in numerous inflammatory diseases, and inhibition of cGAS-STING signaling has attracted significant interest as a therapeutic approach to attenuate aberrant inflammation. Proteolysis-targeting chimeras (PROTACs) have become popular modalities for catalyzing the degradation of proteins of interest, thus inhibiting their function. Herein, the design, synthesis, and characterization of noncovalent catalytic STING PROTACs based on a known diphenyl-dihydroisoquinolone STING inhibitory chemotype are reported. The lead from this series (BH690L) exhibits an effective concentration for half-maximal degradation (DC₅₀) of 11.3 nM and a maximum level of degradation observed for a given concentration of PROTAC (D_max) of 0.67, and elicits suppression of downstream markers of inflammation.