Name: Pevonedistat
Brand: BOC Sciences
Price: 349 USD
Availability: MadeToOrder

Purity

≥98% (HPLC)

Solubility

Soluble in DMSO, not soluble in water.

Appearance

White solid powder

Application

Enzyme Inhibitors

ShelfLife

>2 years if stored properly

Storage

Dry, dark and at 0-4°C for short term (days to weeks) or -20°C for long term (months to years).

Shipping

Room temperature in continental US; may vary elsewhere.

IUPACName

[(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate

Synonyms

TAK-924; TAK 924; TAK924; MLN4924; MLN 4924; BAY-73-4506; BAY 73-4506; BAY73-4506

Chemical Name

((1S,2S,4R)-4-(4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate

InChI Key

MPUQHZXIXSTTDU-QXGSTGNESA-N

InChI

InChI=1S/C21H25N5O4S/c22-31(28,29)30-11-14-9-15(10-19(14)27)26-8-7-17-20(23-12-24-21(17)26)25-18-6-5-13-3-1-2-4-16(13)18/h1-4,7-8,12,14-15,18-19,27H,5-6,9-11H2,(H2,22,28,29)(H,23,24,25)/t14-,15+,18-,19-/m0/s1

SMILES

C1CC2=CC=CC=C2C1NC3=C4C=CN(C4=NC=N3)C5CC(C(C5)O)COS(=O)(=O)N

Biological Activity

Pevonedistat (MLN4924) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor with an IC50 of 4.7 nM.

Mechanism

E3 Ligase: Pevonedistat functions as a selective inhibitor of the NEDD8-activating enzyme (NAE), indirectly modulating cullin-RING E3 ligases (CRLs) rather than directly recruiting them. By preventing NEDD8 conjugation, Pevonedistat inactivates CRLs, which alters ubiquitination of multiple substrate proteins.

Target Protein: The primary effect of Pevonedistat is on CRL substrate proteins, including cell cycle regulators such as CDT1, p27, and NRF2. These proteins accumulate due to impaired CRL-mediated ubiquitination, allowing controlled investigation of CRL-dependent degradation pathways in experimental systems.

Degradation Mechanism: Pevonedistat indirectly influences proteasomal degradation by stabilizing CRL substrates that would normally be ubiquitinated. Inhibition of NEDD8 activation prevents substrate recognition by CRLs, reducing proteasome-mediated degradation and leading to accumulation of specific proteins without involving lysosomal pathways.

Applications

• Molecular Glue for Protein Degradation: Pevonedistat acts as a molecular glue to facilitate the targeted degradation of specific proteins by promoting their ubiquitination. This application is crucial for researchers aiming to modulate protein levels in cellular models to study disease mechanisms and identify potential therapeutic targets.

• Enhancing Ubiquitin-Proteasome Pathway: By serving as a molecular glue, Pevonedistat enhances the ubiquitin-proteasome pathway, leading to the selective degradation of proteins involved in cancer cell survival. This makes it an invaluable tool for scientists exploring novel cancer treatment strategies through protein homeostasis manipulation.

• Targeted Degradation in Drug Discovery: Pevonedistat's role as a molecular glue in targeted protein degradation provides a novel approach in drug discovery. Researchers can leverage its unique mechanism to investigate the degradation of proteins that are traditionally considered "undruggable," expanding the potential for new therapeutic developments.

• Mechanistic Studies of Protein Interactions: Utilizing Pevonedistat as a molecular glue enables detailed mechanistic studies of protein-protein interactions. By inducing the degradation of specific protein complexes, researchers can dissect the functional roles of these interactions in various cellular processes, advancing our understanding of complex biological systems.

1.NEDD8-activating enzyme inhibitor, MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis through up-regulation of ATF-4.

Liu X;Jiang Y;Wu J;Zhang W;Liang Y;Jia L;Yu J;Jeong LS;Li L Biochem Biophys Res Commun. 2017 Jun 17;488(1):1-5. doi: 10.1016/j.bbrc.2017.04.122. Epub 2017 Apr 24.

It has been reported that MLN4924 can inhibit cell growth and metastasis in various kinds of cancer. We have reported that MLN4924 is able to inhibit angiogenesis through the induction of cell apoptosis both in vitro and in vivo models. Moreover, Neddylation inhibition using MLN4924 triggered the accumulation of pro-apoptotic protein NOXA in Human umbilical vein endothelial cells (HUVECs). However, the mechanism of MLN4924-induced NOXA up-regulation has not been addressed in HUVECs yet. In this study, we investigated how MLN4924 induced NOXA expression and cellular apoptosis in HUVECs treated with MLN4924 at indicated concentrations. MLN4924-induced apoptosis was evaluated by Annexin V-FITC/PI analysis and expression of genes associated with apoptosis was assessed by Quantitative RT-PCR and western blotting. As a result, MLN4924 triggered NOXA-dependent apoptosis in a dose-dependent manner in HUVECs. Mechanistically, inactivation of Neddylation pathway caused up-regulation of activating transcription factor 4 (ATF-4), a substrate of Cullin-Ring E3 ubiquitin ligases (CRL). NOXA was subsequently transactivated by ATF-4 and further induced apoptosis. More importantly, knockdown of ATF-4 by siRNA significantly decreased NOXA expression and apoptotic induction in HUVECs.

2.H2O2 regulates lung epithelial sodium channel (ENaC) via ubiquitin-like protein Nedd8.

Downs CA;Kumar A;Kreiner LH;Johnson NM;Helms MN J Biol Chem. 2013 Mar 22;288(12):8136-45. doi: 10.1074/jbc.M112.389536. Epub 2013 Jan 28.

Redundancies in both the ubiquitin and epithelial sodium transport pathways allude to their importance of proteolytic degradation and ion transport in maintaining normal cell function. The classical pathway implicated in ubiquitination of the epithelial sodium channel (ENaC) involves Nedd4-2 regulation of sodium channel subunit expression and has been studied extensively studied. However, less attention has been given to the role of the ubiquitin-like protein Nedd8. Here we show that Nedd8 plays an important role in the ubiquitination of ENaC in alveolar epithelial cells. We report that the Nedd8 pathway is redox-sensitive and that under oxidizing conditions Nedd8 conjugation to Cullin-1 is attenuated, resulting in greater surface expression of α-ENaC. This observation was confirmed in our electrophysiology studies in which we inhibited Nedd8-activating enzyme using MLN4924 (a specific Nedd8-activating enzyme inhibitor) and observed a marked increase in ENaC activity (measured as the product of the number of channels (N) and the open probability (Po) of a channel). These results suggest that ubiquitination of lung ENaC is redox-sensitive and may have significant implications for our understanding of the role of ENaC in pulmonary conditions where oxidative stress occurs, such as pulmonary edema and acute lung injury.

3.MLN4924 suppresses lipopolysaccharide-induced proinflammatory cytokine production in neutrophils in a dose-dependent manner.

Jin J;Jing Z;Ye Z;Guo L;Hua L;Wang Q;Wang J;Cheng Q;Zhang J;Xu Y;Wei L Oncol Lett. 2018 May;15(5):8039-8045. doi: 10.3892/ol.2018.8333. Epub 2018 Mar 23.

Neddylation is a ubiquitination-like pathway. It has been reported that neddylation inhibition with the pharmacological agent MLN4924 potently uppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, by preventing the degradation of phosphorylated inhibitor of κB (p-IκB) in macrophages. However, whether neddylation serves a similar role in neutrophils remains unknown. In the present study MLN4924 treatment led to the accumulation of P-IκBα in neutrophils as well as the decreased production of TNF-α, IL-6 and IL-1β in response to LPS, in a dose-dependent manner. The viability of neutrophils was only marginally affected in the same conditions, without statistical significance. Furthermore, the nuclear factor (NF)-κB inhibitor JSH-23 mimicked the effects of MLN4924 in neutrophils, and the inhibitory effects of MLN4924 on LPS-induced proinflammatory cytokine production diminished in the presence of JSH-23. Thus, the results of the present study suggest that neddylation inhibition suppresses neutrophil function by suppressing the NF-κB signaling pathway.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	2.2547 mL	11.2734 mL	22.5469 mL
5 mM	0.4509 mL	2.2547 mL	4.5094 mL
10 mM	0.2255 mL	1.1273 mL	2.2547 mL
50 mM	0.0451 mL	0.2255 mL	0.4509 mL

What is the mechanism of action of Pevonedistat?

Pevonedistat inhibits the degradation of key regulatory proteins by blocking the ubiquitin-mediated proteasomal degradation pathway.

7/6/2016

How does Pevonedistat inhibit pancreatic cancer cells?

Pevonedistat causes G2-phase defect and subsequent cell apoptosis in pancreatic cancer cells by suppressing the ubiquitination and degradation of Wee1, p27, and p21 and inducing their accumulation.

24/7/2018

a ligand-independent manner

As expected, Pevonedistat activates p53-dependent, TRAIL-R2-, and caspase-8-mediated apoptosis in a ligand-independent manner.

5/9/2019

apoptotic effect

In my experiment, Pevonedistat can prime the mitochondria for apoptosis by upregulating the levels of NOXA, BAX, BAK, and BID.

30/6/2020

Stock concentration: *

Desired final volume: *

Desired concentration: *

* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂