Design, Synthesis, and Pharmacological Evaluation of cGAS/HDAC Dual Inhibitors for Treatment of Autoimmune Diseases

cGAS overactivation is linked to various inflammatory and autoimmune diseases. Recent studies identify HDACs as critical regulators of cGAS, suggesting that dual cGAS/HDAC inhibition could be a novel therapeutic strategy. Herein, we report the identification of an HDAC/cGAS dual inhibitor, 31h, containing a hydroxamic acid moiety. This compound exhibited potent inhibitory activity against human and mouse cGAS (IC₅₀: 0.17 and 1.80 μM, respectively) and moderate activity against HDAC3 and HDAC6 (IC₅₀: 1.2 and 0.4 μM, respectively). Mechanistically, 31h directly suppresses cGAS activity and increases its acetylation levels via HDAC3 inhibition. This dual-action profile resulted in robust therapeutic efficacy in murine models of inflammatory bowel disease and Aicardi-Goutières syndrome. Collectively, 31h represents the first cGAS/HDAC dual inhibitor, offering a promising lead for further investigation into cGAS-dependent disorders.