U18666A

Protein target name:

NPC1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

0.1-1 uM

Probe Availability

MedChemExpress

TOCRIS

Sigma-Aldrich

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Subclass:

Intracellular Cholesterol Transporter

HUGO ID:

HGNC:7897

Entrez gene ID:

4864

UNIPROT ID:

O15118

Target alias:

NPC1, "Niemann-Pick disease, type C1"

Probe Details

Chemical Probes Portal ID:

CPP1280

Probe alias:

U 18666A; 3039-71-2; U18666A; NSC 70801; U-18666A; NSC-70801

PubChem CID:

9954082

ChEMBL ID:

CHEMBL2354929

SMILES string:

CCN(CC)CCOC1CCC2(C3CCC4(C(C3CC=C2C1)CCC4=O)C)C.Cl

InChi Key:

GZFYZYBWLCYBMI-MYZJJQSMSA-N

Control compound:

Compound A

Validation in Cells and Model Organisms

In cell validation

On target activity in cells

Potency in cells:

30 nM

Potency assay (cells):

Cholesterol esterification and proteolytic cleavage of SREBP-2

Target engagement assay (cells):

Degradation of 125I-LDL inhibition control

In vivo validation

Organism:

Rat

Dose:

10 mg/Kg

Route of delivery:

Subcutaneous

Primary Reference

Reference (doi):

10.7554/eLife.12177

Reference (PMID):

26646182

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

More data is needed for this compound to judge it as a probe. No panel data is provided neither within target family nor outside. Crosslinking experiments have identified the proposed target. Analogues and some crude SAR are reported in the paper. Less active analogues were used as controls. Lacking data to be able to judge in vivo dosing. The compound seems to have been in vivo as a Seladin-1 inhibitor 24-dehydrocholesterol reductase https://doi.org/10.1159/000488765: Moreover it also inhibits the microsomal antiestrogen binding site of AEBS a hetero-oligomeric complex, composed of 3β-hydroxysterol-Δ8-Δ7-isomerase (D8D7I) and 3β-hydroxysterol-Δ7-reductase (DHCR7) with a Ki =84 nM and cholesterol-5,6-epoxide hydrolase ChEH with a Ki= 90 nM DOI: 10.1073/pnas.1002922107

Mar 13 2021 - 5:27pm

With very little characterization, it is difficult to judge the quality of this compound. There is no selectivity screening and only a single on-target cellular assay. The data has not been validated using an orthogonal assay format. The animal data is also sparse and lacks PK values that would be informative related to its use.

Mar 13 2021 - 5:31pm

U18666A is a chemical probe for NPC1 that transports cholesterol from the lysosomal membrane. In cells U18666A inhibits cholesterol transesterification and SREBP2 processing at nM concentrations. U18666A has been shown to bind its target NPC1 by using a benzophenone derivative of U18666A that was crosslinked to NPC1. The target protein NPC1 is important in cholesterol homeostasis maintenance and Ebola virus infection, however, the U18666A binding site does not seem to be required for virus entry.
In vivo studies need further fine tuning of dosing and delivery route. Literature suggests: Feline peritonitis virus in vivo exposure 2.5mg/kg (31963705), ebola virus pathogenesis 2mg/kg in vivo (26015498), prion propagation in vivo 10mg/kg (17409533). Pharmacokinetic and pharmacodynamic studies would be beneficial.

Mar 20 2021 - 8:38am

U18666A

Probe Availability

Probe Information

Target Details

NPC1, "Niemann-Pick disease, type C1"

Probe Details

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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U18666A

Probe Availability

Probe Information

Target Details

NPC1, "Niemann-Pick disease, type C1"

Probe Details

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?