Discovery of\n1,2,4-Triazole-3-thione Derivatives as\nPotent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis\nand Remodeling

DCN1, a critical co-E3 ligase during the neddylation\nprocess, is\noveractivated in many diseases, such as cancers, heart failure as\nwell as fibrotic diseases, and has been regarded as a new target for\ndrug development. Herein, we designed and synthesized a new class\nof 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit <b>HD1</b> identified from high-throughput screening and optimized\nthrough numerous structure–activity-relationship (SAR) explorations. <b>HD2</b> (IC<sub>50</sub>= 2.96 nM) was finally identified and\nrepresented a highly potent and selective DCN1 inhibitor with favorable\nPK properties and low toxicity. Amazingly, <b>HD2</b> effectively\nrelieved Ang II/TGFβ-induced cardiac fibroblast activation <i>in vitro</i>, and reduced ISO-induced cardiac fibrosis as well\nas remodeling <i>in vivo</i>, which was linked to the inhibition\nof cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings\nunveil a novel 1,2,4-triazole-3-thione-based derivative <b>HD2</b>, which can be recognized as a promising lead compound targeting\nDCN1 for cardiac fibrosis and remodeling.