Histone deacetylase 3 (HDAC3) plays a pivotal role in inflammation by regulating transcriptional programs and promoting NLRP3 inflammasome activation. Here, we report the discovery of GS-1, a covalent HDAC3 degrader derived from a previously reported 18β-glycyrrhetinic acid derivative A18 via structural optimization. It selectively degraded HDAC3 in THP-1 cells, with minimal enzymatic HDAC inhibition and low cytotoxicity. LC-MS/MS analysis revealed covalent modification at Lys367, and molecular simulations indicated that it was located at a noncatalytic site and interacted with surrounding residues. GS-1 demonstrated favorable pharmacokinetics and excellent in vivo tolerability. Mechanistically, GS-1 suppressed NLRP3 inflammasome activation by degrading HDAC3, thereby reducing the maturation of IL-1β and caspase-1. In murine models, GS-1 significantly alleviated inflammation in LPS-induced endotoxic shock, DSS-induced colitis, and MSU-induced gout, showing potent efficacy and excellent safety profiles. These findings establish GS-1 as a promising chemical probe and therapeutic lead for anti-inflammation through HDAC3 degradation.
Qin et al. (Wed,) studied this question.