2. Academic Validation
  3. Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling

Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling

  • J Med Chem. 2024 Aug 19. doi: 10.1021/acs.jmedchem.4c00713.
Zhang-Xu He 1 2,  Ge Gao 2,  Hui Qiao 2,  Guan-Jun Dong 2,  Zengyangzong Dan 2,  Ya-Lan Li 2,  Yu-Ruo Qi 2,  Qian Zhang 2,  Shuo Yuan 3,  Hong-Min Liu 2,  Jianzeng Dong 4,  Wen Zhao 2,  Li-Ying Ma 2 5 6
Affiliations

Affiliations

  • 1 Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
  • 2 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 3 Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
  • 4 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
  • 5 China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China.
  • 6 Key Laboratory of Cardiocerebrovascular Drugs, Zhumadian 463000, Henan Province, China.
PMID: 39158077 DOI: 10.1021/acs.jmedchem.4c00713
Abstract

DCN1, a critical co-E3 Ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

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