Last update 01 Nov 2024

NAE1

Last update 01 Nov 2024

Basic Info

Synonyms

Amyloid beta precursor protein-binding protein 1, 59 kDa, Amyloid protein-binding protein 1, APP-BP1

+ [6]

Introduction

Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. The covalent attachment of NEDD8 to target proteins is known as 'neddylation' and the process is involved in the regulation of cell growth, viability and development.

Drugs associated with NAE1

X-10

Target

NAE1

Mechanism

NAE1 modulators

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

BSCHL-2046

Target

NAE1 x Ubiquitin-protein ligases

Mechanism

NAE1 modulators [+2]

Active Org.

University of California

Originator Org.

University of California

Active Indication

Prostatic Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NAE1

100 Translational Medicine associated with NAE1

0 Patents (Medical) associated with NAE1

139

Literatures (Medical) associated with NAE1

01 Dec 2024·Journal of Molecular and Cellular Cardiology

Inhibition of cardiomyocyte neddylation impairs embryonic cardiac morphogenesis

Article

Author: Su, Huabo ; Zou, Jianqiu ; Zhou, Jiliang ; Zambrano-Carrasco, Josue ; Kim, Il-Man ; Kim, Il-man ; Littlejohn, Rodney ; Li, Jie ; Yao, Yali

Heart development is a complex spatiotemporal process involving a series of orchestrated morphogenic events that result in the formation of an efficient pumping organ. How posttranslational mechanisms regulate heart development remains poorly understood. Therefore, we investigate how neddylation, the attachment of NEDD8 to target proteins, coordinates cardiogenesis. Abrogation of neddylation by deleting Nae1 in the heart via Sm22α^Cre led to early embryonic lethality. Mutant hearts exhibited deficits in trabeculation and expansion of the compact layer due to reduced cardiomyocyte proliferation, which was linked to abnormal Notch signaling in the developing heart. Overall, our findings demonstrate an essential role for neddylation in cardiogenesis.

01 Oct 2024·SLAS Discovery

Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor

Article

Author: Teicher, Beverly A. ; Doroshow, James H. ; Coussens, Nathan P. ; Doroshow, James H ; Moscow, Jeffrey A. ; Fang, Jianwen ; Silvers, Thomas ; Jones, Eric ; Teicher, Beverly A ; Chen, Li ; Dexheimer, Thomas S ; Morris, Joel ; Jones, Eric M ; Moscow, Jeffrey A ; Coussens, Nathan P ; Dexheimer, Thomas S.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes of drug transporters and metabolic enzymes to detoxify small molecule xenobiotics. It has a complex role in cancer biology, influencing both the progression and suppression of tumors by modulating malignant properties of tumor cells and anti-tumor immunity, depending on the specific tumor type and developmental stage. This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials. To identify small molecule anticancer agents that might be combined with AhR antagonists for cancer therapy, a high-throughput combination screen was performed using multi-cell type tumor spheroids grown from malignant cells, endothelial cells, and mesenchymal stem cells. The AhR selective antagonists BAY 2416964, GNF351, and CH-223191 were tested individually and in combination with twenty-five small molecule anticancer agents. As single agents, BAY 2416964 and CH-223191 showed minimal activity, whereas GNF351 reduced the viability of some spheroid models at concentrations greater than 1 µM. The activity of most combinations aligned well with the single agent activity of the combined agent, without apparent contributions from the AhR antagonist. All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor. These combinations were active in spheroids containing bladder, breast, ovary, kidney, pancreas, colon, and lung tumor cell lines. The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib.

01 Oct 2024·Biomedicine & Pharmacotherapy

Discovery of small molecule inhibitors of neddylation catalyzing enzymes for anticancer therapy

Review

Author: Qin, Xiangshuo ; Han, Xin ; Sun, Yi

Protein neddylation, a type of post-translational modifications, involves the transfer of the ubiquitin-like protein NEDD8 to the lysine residues of a target substrate, which is catalyzed by the NEDD8 activating enzyme (E1), NEDD8 conjugating enzyme (E2), and NEDD8 ligase (E3). Cullin family proteins, core components of Cullin-RING E3 ubiquitin ligases (CRLs), are the most well-known physiological substrates of neddylation. CRLs, activated upon cullin neddylation, promote the ubiquitination of a variety of key signaling proteins for proteasome degradation, thereby regulating many critical biological functions. Abnormal activation of neddylation enzymes as well as CRLs has been frequently observed in various human cancers and is associated with poor prognosis for cancer patients. Consequently, targeting neddylation has emerged as a promising strategy for the development of novel anticancer therapeutics. This review first briefly introduces the properties of protein neddylation and its role in cancer, and then systematically summarizes all reported chemical inhibitors of the three neddylation enzymes, providing a focused, up to date, and comprehensive resource in the discovery and development of these small molecule inhibitors.

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NAE1

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