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

  • J Med Chem. 2026 Jun 25;69(12):14601-14626. doi: 10.1021/acs.jmedchem.6c00583.
Zihua Zhou  1  2  3 ,  Mingjie Chen  1  2 ,  Shuyue Lei  4  5 ,  Meng Wang  6 ,  Chunyong Ding  1  2 ,  Zilan Song  1  2 ,  Wei Tang  4  5 ,  Ao Zhang  1  2  7  8
Affiliations
  • 1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.
  • 3. Zhejiang Pharmaceutical University, Ningbo 315100, China.
  • 4. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6. School of Medicine, Anhui University of Science and Technology, Huainan 232001, China.
  • 7. The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China.
  • 8. State Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., 200 Taicang Road, Shanghai 200020, P. R. China.
PMID: 42268702 DOI: 10.1021/acs.jmedchem.6c00583
Abstract

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.

Products