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.