NMS-873

Protein target name:

VCP

Mechanism of action:

Allosteric Inhibitor

Recommended Concentration for use in cells:

Up to 5 uM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

ATPase

Subclass:

AAA+

HUGO ID:

HGNC:12666

Entrez gene ID:

7415

UNIPROT ID:

P55072

Target alias:

p97; TERA; CDC48; FTDALS6

Probe Details

Chemical Probes Portal ID:

CPP2366

Probe alias:

cpd 6

PubChem CID:

71521142

ChEMBL ID:

CHEMBL2311578

SMILES string:

CC(C=C(OCC1=NN=C(SC2CCCC2)N1C3=CC=CN=C3)C=C4)=C4C5=CC=C(S(=O)(C)=O)C=C5

InChi Key:

UJGTUKMAJVCBIS-UHFFFAOYSA-N

Orthogonal probe:

CB-5083LC-1028

Physico-chemical properties

NMR:

1H-NMR (400 MHz, DMSO-d6): δ 8.75-8.71 (m, 2H), 8.03 (m, 1H), 7.95 (m, 2H), 7.63 (m, 1H), 7.57 (m, 2H), 7.14 (d, J = 8.30 Hz, 1H), 6.83-6.79 (m, 2H), 5.18 (s, 2H), 3.83 (m, 1H), 3.25 (s, 3H), 2.18 (s, 3H), 2.07 (m, 2H), 1.67-1.53 (m, 6H);

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

30 nM low ATP, 20 nM high ATP, 20 nM C522T

Potency assay:

ATPase Assay

Off target activity

Probe Selectivity in Vitro:

Selective (IC50 >10 μM) against all of the AAA ATPases

Outside target family: selective against HSP90 and 53 kinases analyzed

In cell validation

On target activity in cells

Potency in cells:

IC50

400 nM HCT116, 700 nM HeLa, 80-2000 nM

Potency assay (cells):

antiproliferative activity assay

Target engagement assay (cells):

Anti-proliferation assay; accumulation of poly-Ub proteins and stabilization of cyclin E and Mcl-1 in the low µM range; activation of the UPR, as assessed by increased GRP78, C/EBP homologous protein (CHOP) or its transcriptional target GADD34; induction of CHOP in low µM range.

Primary Reference

Reference (doi):

10.1038/nchembio.1313

Reference (PMID):

23892893

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB Comments

Limited selectivity data (AAA ATPase, HSP90 and 53 kinases) and no wide ligand profiling data. The high lipophilicity of the compound is a concern regarding off-target selectivity. No data regarding in-cell occupancy of VCP and its relation to the biomarkers or antiproliferation phenotype that might describe the shift in potency from 30 nM in vitro.

Sep 23 2021 - 10:04am

In vitro selectivity data within the target family (all AAA ATPases) and limited selectivity outside the target family (HSP90 and 53 kinases) are presented. However, an in-cell target engagement study using NMS-873 is lacking. Recent publications call for caution regarding potential polypharmacology and off-target effects of this compound: broad antiviral activity against influenza A and B viruses (Zhang et al) and dual inhibition of mitochondrial oxidative phosphorylation (Bouwer et al) have been reported. Zhang et al. Eur J Pharm Sci 2019, 133, 86–94. Bouwer et al. Biochimie 2021, 185, 33–42

Sep 30 2021 - 10:54am

NMS-873

Probe Availability

Probe Information

Target Details

p97; TERA; CDC48; FTDALS6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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NMS-873

Probe Availability

Probe Information

Target Details

p97; TERA; CDC48; FTDALS6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?