CB-5083

Protein target name:

VCP

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 1 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:

CPP2365

Probe alias:

JDP, cpd 71

PubChem CID:

73051434

ChEMBL ID:

CHEMBL3747513

SMILES string:

O=C(C1=CC=CC2=C1C=C(C)N2C3=NC(NCC4=CC=CC=C4)=C(COCC5)C5=N3)N

InChi Key:

RDALZZCKQFLGJP-UHFFFAOYSA-N

Control compound:

cpd 7

Orthogonal probe:

NMS-873LC-1028

Physico-chemical properties

NMR:

1H NMR (400 MHz, CD3OD): δ 7.73 (d, J = 8.4 Hz, 1H, Ph), 7.46 (d, J = 7.6 Hz, 1H, Ph), 7.34–7.29 (m, 4H, Ph), 7.27–7.24 (m, 1H, Ph), 6.97 (t, J = 7.6 Hz, 1H, Ph), 6.78 (s, 1H, 3-H of indole), 4.71 (s, 2H, CH2Ph), 4.64 (s, 2H, OCH2), 4.05 (t, J = 5.6 Hz, 2H, OCH2CH2), 2.82 (t, J = 5.6 Hz, 2H, OCH2CH2), 2.45 (s, 3H, Me).

13C NMR (400 MHz, CD3OD): δ 174.06, 160.71, 160.45, 156.45, 140.82, 140.42, 138.91, 129.58, 128.62, 127.95, 127.83, 125.75, 122.06, 121.91, 117.57, 109.72, 105.48, 65.68, 64.08, 45.24, 31.78, 15.72.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

11 nM

Potency assay:

ATPase assay

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

6MCK

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

DNAPK 500 nMPDE6 80 nM

Probe Selectivity in Vitro:

off target ATPase inhibition 0/175, Kinase inhibition: 1/173; DNAPK (IC50 = 500 nM; inactive in cells)

In cell validation

On target activity in cells

Potency in cells:

IC50

115–2000 nM (C), 150–800 nM

Potency assay (cells):

Cell Proliferation assay (>300 tumor cell lines tested)(C), IF assay on poly Ub accumulation (12 tumor cell lines tested)

In vivo validation

Organism:

Mouse

Dose:

3 (IV)- 25 (PO) mg/Kg, Reviewer recommended: 100 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

2.83 (IV), 2.56 (PO) h

Systemic clearance:

5.9 (IV) mL/min/kg

Cmax:

7.95 uM

Tmax:

0.5 h

Vss:

418 (IV) mL/kg

AUC:

8.42 (IV), 28.94 (PO) h·μM

Bioavailability:

41 %

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.5b01346

Reference (PMID):

26565666

Endorsed probe

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

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

CB-5083 has been well characterized in terms of its PK profile and cellular activity. In terms of selectivity, it appears to have only been counter-screened in ATPase and kinase panels. The subsequent report by others that it inhibits PDE6, and is indeed only 8-fold selective over PDE6, serves to provide a reminder that any results obtained with CB-5083 should be interpreted with caution as other pharmacology may be at play.

Sep 13 2021 - 2:58pm

Choice of concentration is cell-line dependent and is also indication-dependent, most likely. If cytotoxicity is not a desired pharmacological response, using submicromolar concentration may be preferred. Testing at 2 or 3 concentrations would be the most informative approach in such a case. While the listed dose may be suitable, a higher dose - 75 mg/kg QD in mice - is also tolerated and may thus be explored, depending on the indication.

Sep 23 2021 - 10:01am

This is a well-characterized probe recommended for use in cells and in mice. A wide range of biochemical and cellular measurements support a direct effect on VCP/p97. Notably, resistant alleles have been identified by selection from HCT116 cells. Mouse PK (IV and PO) is available, and numerous studies measuring VCP modulation and downstream cancer phenotypes have been reported using oral administration of 100 mpk CB-5083.

Oct 26 2021 - 10:10am

CB-5083

Probe Availability

Probe Information

Target Details

p97; TERA; CDC48; FTDALS6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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CB-5083

Probe Availability

Probe Information

Target Details

p97; TERA; CDC48; FTDALS6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?