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Last update 08 May 2025

DCN1

Last update 08 May 2025

Basic Info

Synonyms

DCN1, DCN1-like protein 1, DCNL1

+ [10]

Introduction

Part of an E3 ubiquitin ligase complex for neddylation (PubMed:18826954). Promotes neddylation of cullin components of E3 cullin-RING ubiquitin ligase complexes (PubMed:19617556, PubMed:23201271, PubMed:23401859, PubMed:26906416). Acts by binding to cullin-RBX1 complexes in the cytoplasm and promoting their nuclear translocation, enhancing recruitment of E2-NEDD8 (UBE2M-NEDD8) thioester to the complex, and optimizing the orientation of proteins in the complex to allow efficient transfer of NEDD8 from the E2 to the cullin substrates. Involved in the release of inhibitory effets of CAND1 on cullin-RING ligase E3 complex assembly and activity (PubMed:25349211, PubMed:28581483). Acts also as an oncogene facilitating malignant transformation and carcinogenic progression (By similarity).

Drugs associated with DCN1

SK-464

Target

DCN1 x UBC12

Mechanism

DCN1 inhibitors [+1]

Active Org.

Zhengzhou University

Originator Org.

Zhengzhou University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

DI 1548

Target

DCN1

Mechanism

DCN1 inhibitors

Active Org.

University of Michigan

Originator Org.

University of Michigan

Active Indication

Chemical and Drug Induced Liver Injury

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

DN-2

Target

DCN1 x UBC12

Mechanism

DCN1 inhibitors [+1]

Active Org.

Zhengzhou University [+1]

Originator Org.

Piistech

Active Indication

Myocardial fibrosis

Inactive Indication

Acute Myeloid Leukemia

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DCN1

100 Translational Medicine associated with DCN1

0 Patents (Medical) associated with DCN1

148

Literatures (Medical) associated with DCN1

12 Feb 2025·Clinical Science

Blockade of neddylation through targeted inhibition of DCN1 alleviates renal fibrosis

Article

Author: Liu, Zhangsuo ; Huo, Jin-Ling ; Feng, Qi ; Pan, Shaokang ; Liu, Dongwei ; Fu, Wenjia

Neddylation is a process of attaching neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to substrates for the protein function modulation via enzymatic cascades involving NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3). Defective in cullin neddylation 1 (DCN1) serves as a co-E3 ligase, which can simultaneously bind E2 UBE2M and cullin proteins to stabilize the catalytic center of the Cullin-Ring E3 ligase complex, thereby promoting cullin neddylation. Neddylation is reported to be activated in diverse human diseases, and inhibition of protein neddylation has been regarded as a promising anticancer therapy. However, whether neddylation participates in renal fibrosis and whether blockade of neddylation through targeted inhibition of DCN1 play effects on renal fibrosis remains unknown. In the present study, an NEDD8 overexpressed plasmid, DCN1 small interfering RNAs, DCN1-specific inhibitor NAcM-OPT, human renal tubular epithelial cells (HK-2), rat kidney fibroblasts (NRK-49F), RNA sequencing, unilateral ureteral obstruction (UUO), and unilateral ischemia-reperfusion injury (UIRI) mouse renal fibrosis models were used. Herein, we first showed that neddylation was activated in renal fibrosis. Neddylation blockade through DCN1 deficiency alleviated TGFβ1-induced up-regulation of fibronectin and α-SMA in HK-2 and NRK-49F cells. Importantly, DCN1 inhibition attenuated UUO- and UIRI-induced mouse renal fibrosis. Further studies revealed that DCN1 loss selectively inhibited cullin3 neddylation and induced its substrate NRF2 accumulation, thereby inhibiting TGFβ-Smad2/3 signaling pathway. Overall, blockade of neddylation through targeted inhibition of DCN1 contributes to alleviating renal fibrosis in vitro and in vivo, which may constitute a novel therapeutic strategy for renal fibrosis.

14 Nov 2024·Journal of Medicinal Chemistry

Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling

Article

Author: Qiao, Hui ; Ma, Li-Ying ; Li, Ya-lan ; Dan, Zengyangzong ; Zhao, Wen ; Gao, Ge ; Yuan, Shuo ; Dong, Guan-jun ; Dong, Jianzeng ; Zhang, Qian ; Liu, Hong-Min ; He, Zhang-Xu ; Qi, Yu-ruo

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC₅₀= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

01 Oct 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

DCUN1D1 and neddylation: Potential targets for cancer therapy

Review

Author: Donaldson, Lara ; de Vasconcellos, Jaira F ; Foret, Chiara L M ; Zerbini, Luiz F ; Paccez, Juliano D

Cancer affects millions of people and understanding the molecular mechanisms related to disease development and progression is essential to manage the disease. Post-translational modification (PTM) processes such as ubiquitination and neddylation have a significant role in cancer development and progression by regulating protein stability, function, and interaction with other biomolecules. Both ubiquitination and neddylation are analogous processes that involves a series of enzymatic steps leading to the covalent attachment of ubiquitin or NEDD8 to target proteins. Neddylation modifies the CRL family of E3 ligase and regulates target proteins' function and stability. The DCUN1D1 protein is a regulator of protein neddylation and ubiquitination and acts promoting the neddylation of the cullin family components of E3-CRL complexes and is known to be upregulated in several types of cancers. In this review we compare the PTM ubiquitination and neddylation. Our discussion is focused on the neddylation process and the role of DCUN1D1 protein in cancer development. Furthermore, we provide describe DCUN1D1 protein and discuss its role in pathogenesis and signalling pathway in six different types of cancer. Additionally, we explore both the neddylation and DCUN1D1 pathways as potential druggable targets for therapeutic interventions. We focus our analysis on the development of compounds that target specifically neddylation or DCUN1D1. Finally, we provide a critical analysis about the challenges and perspectives in the field of DCUN1D1 and neddylation in cancer research. KEY POINTS: Neddylation is a post-translational modification that regulates target proteins' function and stability. One regulator of the neddylation process is a protein named DCUN1D1 and it is known to have its expression deregulated in several types of cancers. Here, we provide a detailed description of DCUN1D1 structure and its consequence for the development of cancer. We discuss both the neddylation and DCUN1D1 pathways as potential druggable targets for therapeutic interventions and provide a critical analysis about the challenges and perspectives in the field of DCUN1D1 and neddylation in cancer research.

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