Discovery of a Covalent HDAC3 Degrader with Excellent Anti-Inflammatory Activity and NLRP3 Inflammasome Suppression

  • J Med Chem. 2026 Mar 26;69(6):6528-6545. doi: 10.1021/acs.jmedchem.5c02513.
Huanhuan Qin  1 ,  Yue Shi  1 ,  Rulong Liu  1 ,  Bing Wang  1 ,  Luhao Guo  1 ,  Guizhou Hao  2 ,  Guimin Zhang  3 ,  Dan Liu  1 ,  Linxiang Zhao  1 ,  Min Huang  1  4  5
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Shandong Engineering Research Center of Complex Injectables, Shandong New Time Pharmaceutical Co., Ltd., No. 1, North Outer Ring Road, Feixian Area, Linyi City 273400, Shandong, China.
  • 3. National Engineering Laboratory of High Level Expression in Mammalian Cells State Key Laboratory, Lunan Pharmaceutical Group Co., Ltd., Linyi 27600, Shandong, China.
  • 4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
  • 5. Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China.
PMID: 41812251 DOI: 10.1021/acs.jmedchem.5c02513
Abstract

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.

Products