Pevonedistat Chemical Properties

Melting point:

161-163°C

Boiling point:

721.0±70.0 °C(Predicted)

Density 

1.62

storage temp. 

-20°C Freezer

solubility 

Soluble in DMSO (up to 10 mg/ml).

form 

solid

pka

9.35±0.70(Predicted)

color 

White

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.

InChIKey

MPUQHZXIXSTTDU-QXGSTGNESA-N

SMILES

S(N)(OC[C@@H]1C[C@@H](N2C3C(C=C2)=C(N[C@@H]2C4=C(C=CC=C4)CC2)N=CN=3)C[C@@H]1O)(=O)=O

Pevonedistat Usage And Synthesis

Description

MLN4924 (905579-51-3) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor.1?It disrupts cullin-RING ligase-mediated protein turnover leading to apoptosis in human tumor cells. Suppresses the growth of human tumor xenografts in mice.2?Upregulates PD-L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma.3?Modulates tumor microenvironment.4?Cell permeable.

Chemical Properties

White Solid

Uses

A potent and selective inhibitor of NAE. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. The ubiquitin-proteasome pathway mediates the destruction of unwanted proteins. Potent NAE inhibitor; NEDD8 E1 Activating Enzyme Inhibitor.

Definition

ChEBI: Pevonedistat is a pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine which is substituted by a (1S)-2,3-dihydro-1H-inden-1-ylnitrilo group at position 4 and by a (1S,3S,4S)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl group at position 7. It is a potent and selective NEDD8-activating enzyme inhibitor with an IC50 of 4.7 nM, and currently under clinical investigation for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes. It has a role as an apoptosis inducer and an antineoplastic agent. It is a pyrrolopyrimidine, a secondary amino compound, a member of cyclopentanols, a sulfamidate and a member of indanes.

Enzyme inhibitor

This first-in-class small molecule inhibitor (FW = 443.52 g/mol; CAS 905579-51-3; Solubility = 10 mg/mL DMSO), also named MLN4924 and [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3- d]pyrimidin-7-yl]-2-hydroxycyclopentyl]sulfamate methyl ester, targets Nedd8 activating enzyme, or NAE (IC50 = 4.7 nM), with much weaker action against UAE (IC50 = 1.5 μM), SAE (IC50 = 8.2 μM), and UBA6 (IC50 = 1.8 μM). In most cancer cells, pevonedistat treatment results in the induction of DNA re-replication, resulting in DNA damage and cell death. MLN4924 also exhibits an alternative mechanism of action. Treatment of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cells with pevonedistat resulted in rapid accumulation of pIkBa, decrease in nuclear p65 content, reduction of transcriptional activity of NF-kB (or nuclear factor k-light-chain-enhancer of activated B cells), and G1 arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kB pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. Pevonedistat also inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin-ligase and blocking SIVmac replication in myeloid cells, therebyindicating the potential efficacy of inhibiting neddylation as an antiretroviral strategy

storage

Store at -20°C

Background

MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme. The NAE is part of the NEDD8 conjugation pathway that involves the ubiquitin-like NEDD8 protein and cullin-RING ligases. The NAE is responsible for the covalent attachment of NEDD8 to cullin proteins, termed neddylation, resulting in a conformational change within the CRL, analogous to ubiquitination. This is a reversible, multi-step process responsible for cell cycle progression and survival pathways in cancer cells. The inhibition of NAE by MLN4924 induces apoptosis in human tumor cells and reduces human tumor xenograft growth in mice.

References

[1] TERESA A. SOUCY. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer[J]. Nature, 2009, 458 7239: 732-736. DOI:10.1038/nature07884
[2] MICHAEL A MILHOLLEN. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma.[J]. Blood, 2010: 1515-1523. DOI:10.1182/blood-2010-03-272567
[3] SHAOLONG ZHOU. Neddylation inhibition upregulates PD-L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma[J]. International Journal of Cancer, 2019, 145 3: 763-774. DOI:10.1002/ijc.32379
[4] LISHA ZHOU. Neddylation: a novel modulator of the tumor microenvironment.[J]. Molecular Cancer, 2019: 77. DOI:10.1186/s12943-019-0979-1

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