2. Academic Validation
  3. Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects

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

  • J Med Chem. 2022 Jan 13;65(1):163-190. 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
Affiliations

Affiliations

  • 1 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, Henan 450001, P. R. China.
  • 2 China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China.
PMID: 34939411 DOI: 10.1021/acs.jmedchem.1c01207
Abstract

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.

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