Pevonedistat

Reagent Authentication Certificate:

Chemical Probes Portal Pevonedistat.pdf

Protein target name:

UBA3

Mechanism of action:

AntagonistPevonedistat-NEDD8 covalent adduct inhibits NAE

Recommended Concentration for use in cells:

0.3 uM

Probe Availability

MedChem Express (905579-51-3)

Abcam (905579-51-3)

Cayman (905579-51-3)

Probe Information

Target and Probe Information

Target Details

Target class:

UBA3, NAE2, UBE1C, hUBA3

Probe Details

Chemical Probes Portal ID:

CPP731

Probe alias:

MLN4924; Pevonedistat; MLN 4924; MLN-4924; 905579-51-3; UNII-S3AZD8D215

PubChem CID:

16720766

ChEMBL ID:

CHEMBL1231160

SMILES string:

O=S(OC[C@@H]1C[C@@H](N2C3=NC=NC(N[C@H]4CCC5=C4C=CC=C5)=C3C=C2)C[C@@H]1O)(N)=O

InChi Key:

MPUQHZXIXSTTDU-QXGSTGNESA-N

Orthogonal probe:

ABPA3

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

0.004 uM

Potency assay:

Purified enzyme assay, monitoring the formation of E2-UBL thioester reaction products.

PDB ID for probe-target interaction (3D structure):

1R4N

Off target activity

Potency (off target):

IC50

Off target protein and potency:

UAE: 1.5 uM, SAE: 8.2 uMUBA6: 1.8 uM, ATG7 >10 uM

Potency assay (off target):

Purified enzyme assays monitoring the formation of E2-UBL thioester reaction products.

Probe Selectivity in Vitro:

Pevonedistat had no effect on RNA synthetases in assays monitoring 35S-Met incorporation into newly synthesized proteins. It also had no significant activity against other ATP-dependent proteins (i.e., kinases and adenosine receptors).

In cell validation

On target activity in cells

Potency in cells:

IC50

<0.1 uM

Potency assay (cells):

In HCT-116 cells, pevonedistat dose-dependently decreased Ubcl2-NEDD8 thioester formation and NEDD8-cullin conjugates; it increased CRL substrates (e.g., CDT1, p27, NRF2).

Target engagement assay (cells):

Indirect, inhibition of Ubcl2-NEDD8 thioester formation and NEDD8-cullin conjugates.

Off target activity in cells

Potency assay, off target (cells):

In HCT-116 cells, pevonedistat had no effect on non-CRL substrates (e.g., GADD34, securin, cyclin B, p53, geminin).

In vivo validation

Organism:

Female athymic NCR mice

Dose:

10-60 mg/kg

Route of delivery:

Subcutaneous

Organ of Interest

Organ (O):

HCT-116 xenografts, bone marrow

Target engagement assay:

In both xenografts and bone marrow, pevonedistat dose-dependently decreased NEDD8-cullin levels.

Primary Reference

Reference (doi):

10.1016/j.molcel.2009.12.024 10.1038/nature07884

Reference (PMID):

20129059 19360080

External Resources

Available data:

GDSC1 GDSC2

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

If possible, use Pevonedistat in parallel with a positive or negative control compound.

Jul 5 2017 - 2:27pm

MLN4924 is a potent inhibitor of NEDD8-activating enzyme which is selective for other activating enzymes in the Ubiquitin family of ligases. This probe is active in cellular assays in which Ubc12-NEDD8 and NEDD8-cullin levels were significantly reduced in a dose-dependent manner following doses as low as 100 nM in HCT-116 cells. In vivo studies in mice bearing HCT-116 xenografts using doses as high as 60 mg/kg indicate that the compound is well-tolerated and efficacious in reducing tumor volume.

The lack of a closely-related negative control precludes a higher star rating.

Jul 7 2017 - 1:59pm

MLN4924 is a covalent and cell-permeable inhibitor of NAE. Shows strong selectivity over closely related proteins in biochemical assays as well as reasonable potency in cellular neddylation assays (dose dependency, <100 nM). More direct target engagement analysis (on target, off target) may be warranted to support broader use in cells and model organisms.

Jul 13 2017 - 3:39pm

Pevonedistat

Probe Availability

Probe Information

Target Details

UBA3, NAE2, UBE1C, hUBA3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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Pevonedistat

Probe Availability

Probe Information

Target Details

UBA3, NAE2, UBE1C, hUBA3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?