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

## TL;DR

This paper describes the development of a new molecule that can degrade a key immune protein to reduce inflammation.

## Contribution

The paper introduces noncovalent STING degraders based on a known chemotype, with BH690L showing strong degradation efficacy.

## Key findings

- The lead compound BH690L has a DC50 of 11.3 nM for STING degradation.
- BH690L achieves a Dmax of 0.67, indicating significant degradation potential.
- The compound suppresses downstream markers of inflammation.

## Abstract

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 (Dmax) of 0.67, and elicits suppression of downstream markers of inflammation.

The design, synthesis, and initial biological evaluation of noncovalent stimulator of interferon genes degraders are presented. 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 (Dmax) of 0.67.© 2026 WILEY‐VCH GmbH