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. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

01 Aug 2022·Biochemistry and Cell BiologyQ4 · BIOLOGY

Evaluation of HZX-960, a novel DCN1–UBC12 interaction inhibitor, as a potential antifibrotic compound for liver fibrosis

Q4 · BIOLOGY

Article

Author: Aziz, Shireen ; Zhou, Wenjuan ; Zhao, Wen ; Dong, Guanjun ; He, Zhangxu ; Xu, Jiale ; Gao, Ge ; Ma, Liying

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. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1–UBC12 interaction inhibitor HZX-960 was discovered with an IC50value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor β-induced liver fibrotic responses by reducing the deposition of collagen I and α-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment.

13 Apr 2022·Journal of Biomolecular Structure and Dynamics

Investigating the binding mechanism of piperidinyl ureas inhibitors based on the UBC12-DCN1 interaction by 3D-QSAR, molecular docking and molecular dynamics simulations

Article

Author: Ma, Chaoya ; Liu, Hong-Min ; Yang, Jing ; Zhao, Jiangheng ; Ding, Lina ; Chen, Yujie ; Yan, Ying ; Zang, Jieying ; Gao, Qi-Bing

Neddylation regulates a variety of biological processes by modulating Cullin-RING E3 ubiquitin ligases (CRLs) which is considered to be an important target for human diseases. The activation of CRLs required Cullins Neddylation, which regulated by the interaction of UBC12-DCN1 complex. Here, to investigate the structure-activity relationship and binding mechanism of 41 piperidinyl ureas inhibitors based on the UBC12-DCN1 protein-protein interaction, we carried out molecular modeling studies using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations.Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q²=0.736, r²_ncv=0.978, r²_pred=0.78 (CoMFA), and the best CoMSIA model has q²=0.761, r²_ncv=0.987, r²_pred=0.86. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The results of MM-GBSA indicated the residues of Ile1083, Ile1086, Ala1098, Val1102, Ile1105, Gln1114, Phe1164 and Leu1184 might be the key residues during the process of inhibitors bound to DCN1. This study could provide an important theoretical basis for further developing novel inhibitors design based on UBC12-DCN1 protein-protein interaction. All the results can provide us more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.

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