Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
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.
J Med Chem. 2024 Nov 14;67(21):18699-18723. doi: 10.1021/acs.jmedchem.4c00713. Epub 2024 Aug 19.
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 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. (IC= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation , and reduced ISO-induced cardiac fibrosis as well as remodeling , 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 , which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.
DCN1 是泛素化过程中的关键共 E3 连接酶，在许多疾病中过度激活，如癌症、心力衰竭以及纤维化疾病，并已被视为药物开发的新靶点。在此，我们基于高通量筛选鉴定的命中化合物，设计并合成了一类新型的 1,2,4-三唑-3-硫酮类 DCN1 抑制剂，并通过大量的构效关系（SAR）研究进行了优化。最终鉴定出化合物 （IC=2.96 nM），它是一种高效且选择性的 DCN1 抑制剂，具有良好的 PK 性质和低毒性。令人惊讶的是，它能有效缓解 Ang II/TGFβ诱导的心肌成纤维细胞激活，并减轻 ISO 诱导的心肌纤维化和重构，这与抑制 cullin 3 泛素化及其底物 Nrf2 积累有关。我们的研究结果揭示了一种新型的 1,2,4-三唑-3-硫酮类衍生物，它可被视为一种有前途的靶向 DCN1 治疗心肌纤维化和重构的先导化合物。
