Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects,Journal of Medicinal Chemistry

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Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-23 , DOI: 10.1021/acs.jmedchem.1c01207
Zhang-Xu He ₁ , Qi An ₁ , Bo Wei ₁ , Wen-Juan Zhou ₁ , Bing-Fei Wei ₁ , Yun-Peng Gong ₁ , Xin Zhang ₁ , Ge Gao ₁ , Guan-Jun Dong ₁ , Jin-Ling Huo ₁ , Xin-Hui Zhang ₁ , Fei-Fei Yang ₁ , Hong-Min Liu ₁ , Li-Ying Ma _{1,

2} , Wen Zhao ₁

Affiliation

DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin–RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.

中文翻译：

发现有效且选择性的 2-(苄硫基)嘧啶 DCN1-UBC12 抑制剂，具有抗心脏纤维化作用

DCN1 是一种 co-E3 连接酶，与 UBC12 相互作用，并通过催化 cullin neddylation 来激活 cullin-RING 连接酶 (CRL)。尽管DCN1已被认为是人类疾病的重要治疗靶点，但其在心血管领域的作用仍不清楚。在这里，我们首先发现 DCN1 在经血管紧张素 (Ang) II 处理的分离心脏成纤维细胞 (CF) 中以及在压力超负荷后的小鼠心脏中上调。然后，根据我们之前的工作，对DCN1-UBC12抑制剂进行了基于结构的优化，得到了化合物DN-2 。分子模型研究、HTRF、细胞热位移和免疫共沉淀分析表明， DN-2在分子和细胞水平上特异性靶向 DCN1。重要的是， DN-2有效逆转 Ang II 诱导的心脏成纤维细胞活化，这与抑制 cullin 3 neddylation 相关。我们的研究结果表明 DCN1 抑制在抗心脏纤维化作用中的潜在作用尚未被认识。 DN-2可用作进一步开发的先导化合物。

更新日期：2022-01-13

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