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Pevonedistat

Pevonedistat : NEDD8-activating enzyme inhibitor of UBA3

Structure

Information

  • UBA3
  • Antagonist, Pevonedistat-NEDD8 covalent adduct inhibits NAE

In Vitro Validations

Uniprot ID: Q8TBC4
Target Class: Other post-translational modification
Target SubClass: Ubiquitin-conjugating enzyme
Potency: IC50
Potency Value: 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
Target aliases:
NEDD8-activating enzyme E1 catalytic subunit, UBE1 ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 UAE: 1.5 uM, SAE: 8.2 uM, UBA6: 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).

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).
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 28 Jun 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

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

(last updated: 7 Jul 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 7 Jul 2017 )