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

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

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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