Discovery of a Novel CRBN-Recruiting cGAS PROTAC Degrader for the Treatment of Ulcerative Colitis.

Cyclic GMP-AMP synthase (cGAS), a critical cytosolic DNA sensor initiating innate immune responses in the presence of cytosolic DNA, is increasingly recognized as a promising therapeutic target for ulcerative colitis (UC). Here, we reported the design, synthesis, structure-activity relationship exploration and biological evaluation of a novel class of CRBN-recruiting cGAS-targeting PROTAC degraders. Among them, TH35 exhibited the most favorable degradation profile, achieving potent and selective degradation of cGAS, and markedly attenuated dsDNA-induced activation of cGAS signaling in both human and murine cells, with minimal cytotoxic effects. In vivo, TH35 demonstrated superior therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse model of UC compared to the corresponding cGAS inhibitor, while also displaying acceptable pharmacokinetic properties. Collectively, TH35 as the first CRBN-recruiting cGAS PROTAC holds promise for augmenting anti-inflammatory responses and offers a new avenue for treating cGAS-driven inflammatory diseases.