Synthesis and biological evaluations of novel 18β-glycyrrhetinic acid derivatives as histone deacetylase 3 degraders with anti-inflammatory effects

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118391. doi: 10.1016/j.ejmech.2025.118391.
Huanhuan Qin  1 ,  Rulong Liu  1 ,  Yue Shi  1 ,  Bing Wang  1 ,  Luhao Guo  1 ,  Yiting Wang  1 ,  Guizhou Hao  2 ,  Guimin Zhang  3 ,  Dan Liu  4 ,  Linxiang Zhao  5 ,  Min Huang  6
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, 273400, Linyi City, 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. Electronic address: [email protected].
  • 4. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 5. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 6. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 41273797 DOI: 10.1016/j.ejmech.2025.118391
Abstract

Histone deacetylase 3 (HDAC3) is implicated in inflammatory signaling, and its degradation represents a promising anti-inflammatory strategy. Based on the 18β-glycyrrhetinic acid analogue COOTO-Me, we designed and synthesized a series of novel derivatives and identified Z8 as a potent HDAC3 Degrader. In THP-1 cells, Z8 induced dose- and time-dependent HDAC3 degradation. Multi-omics analysis indicated enrichment of the NOD-like Receptor pathway, and Z8 suppressed the maturation of IL-1β and Caspase-1 in PMA-differentiated THP-1 macrophages, indicating NLRP3 inflammasome inhibition. Z8 showed favorable pharmacokinetics profiles in rats, including high intraperitoneal bioavailability. In vivo, Z8 prolonged survival in LPS-induced septic shock, and alleviated DSS-induced colitis with less weight loss, preserved colon length and restored intestinal barrier function. These results established Z8 as a novel HDAC3 Degrader with excellent anti-inflammatory activity.

Keywords
18β-glycyrrhetinic acid; Anti-inflammation; Degradation; HDAC3.
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