Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2021.113326 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer.
Biomed Pharmacother
April 2024
School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China. Electronic address:
Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo.
View Article and Find Full Text PDFEvaluation of HZX-960, a novel DCN1-UBC12 interaction inhibitor, as a potential antifibrotic compound for liver fibrosis.
Biochem Cell Biol
August 2022
State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety; Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450007, China.
Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of ∼20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis.
View Article and Find Full Text PDFDiscovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects.
J Med Chem
January 2022
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.
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.
View Article and Find Full Text PDFImprovement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.
J Med Chem
May 2021
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40508, United States.
The cullin-RING ubiquitin ligases (CRLs) are ubiquitin E3 enzymes that play a key role in controlling proteasomal degradation and are activated by neddylation. We previously reported inhibitors that target CRL activation by disrupting the interaction of defective in cullin neddylation 1 (DCN1), a CRL neddylation co-E3, and UBE2M, a neddylation E2. Our first-generation inhibitors possessed poor oral bioavailability and fairly rapid clearance that hindered the study of acute inhibition of DCN-controlled CRL activity in vivo.
View Article and Find Full Text PDFDevelopment of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction.
Eur J Med Chem
May 2021
State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China. Electronic address:
Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC value of 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!