Discovery of indole derivatives as STING degraders

Abstract

Aberrant activation of the stimulator of interferon genes (STING) pathway is associated with the development of various inflammatory and autoimmune diseases. Targeting STING for degradation represents a novel strategy for the treatment of these diseases. In this study, we designed and synthesized a series of STING-PROTACs based on a nitro-free covalent warhead and different E3 ligase binders. The representative compound 2h specifically degraded STING protein through the proteasome pathway with a DC₅₀ value of 3.23 μM and exhibited sustained degradation activity over 72 h. Further biological studies demonstrated that compound 2h inhibited STING signaling and effectively suppressed immune-inflammatory cytokines both in vitro and in vivo. Moreover, compound 2h offered better safety compared to its warhead molecule and SP23. Collectively, compound 2h is a potent nitro-free covalent STING degrader and warrants further investigation.