GW3965

Reagent Authentication Certificate:

Chemical Probes Portal GW3965.pdf

Protein target name:

LXR-alpha, LXR-beta

Mechanism of action:

Agonist

Recommended Concentration for use in cells:

100 nM - 1 uM

Probe Information

Target and Probe Information

Target Details

Target class:

Hormone pathway

Subclass:

Hormone receptor

HUGO symbol:

NR1H2 NR1H3

Entrez gene ID:

7376 10062

Target alias:

NR1H2, LXR-b, LXRB, NER, NER-I, RIP15, UNR, NR1H3, LXR-a, LXRA, RLD-1

Probe Details

Chemical Probes Portal ID:

CPP1752

Probe alias:

GW 3965; GW-3965

PubChem CID:

447905

ChEMBL ID:

CHEMBL59030

SMILES string:

C1=CC=C(C=C1)C(CN(CCCOC2=CC=CC(=C2)CC(=O)O)CC3=C(C(=CC=C3)C(F)(F)F)Cl)C4=CC=CC=C4

InChi Key:

NAXSRXHZFIBFMI-UHFFFAOYSA-N

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

EC50

125 nM

Potency assay:

LXRalpha/SRC1 LiSA.

Structure-activity relationship:

Yes some, see J Med Chem paper.

Off target activity

Potency assay (off target):

In a panel of nuclear receptors, GW3965 was only active against LXR and PXR. Panel included: PPARalpha, PPARdelta, PPARgamma, FXR, LXRalpha, LXRbeta, RARalpha, TRbeta, VDR, CAR, AR, GR, MR and PR). In GAL4-reporter assay, GW3965 was >10-fold selective for LXR>PXR.

In cell validation

On target activity in cells

Potency in cells:

EC50

LXR-beta: 30 nM; LXR-alpha: 190 nM

In vivo validation

Organism:

C57BL/6 mice

Dose:

10 mg/kg

Route of delivery:

Oral

Plasma half life:

2 h

Cmax:

12.7 ug/mL

Organ of Interest

Organ (O):

Plasma, small intestine, peripheral macrophages

Target engagement assay:

Indirect: In small intenstine and peripheral macrophages, GW3965 increased ABCA1 7-8 fold. In plasma, GW3965 increased HDL cholesterol 30%.

Primary Reference

Reference (doi):

10.1021/jm0255116

Reference (PMID):

11985463

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

GW3965 has been widely used as a chemical probe for the liver X receptors, alpha and beta. GW3965 is commonly employed in parallel with another LXR agonist such as T1317. T1317 is approximately 10-fold more potent in agonizing the LXRs in cells but suffers from the liability of activity at a handful of other nuclear receptors, notably PXR. GW3965 has properties amenable for in vivo usage.

Aug 7 2017 - 3:59pm

GW3965 is a selective non-steroidal agonist for the LXRa and LXRb receptors. GW3965 is suitable for in vivo use in mouse models where a 10mg/kg oral dose exceeds the LXR EC50. A complementary, structurally orthogonal tool is LXR-623, which could be used in parallel to confirm outcomes.

Aug 11 2017 - 1:42pm

This appears to be a robust and credible probe for the investigation of LXR biology, though the primary literature reference is somewhat sparse in terms of utilization and limitation. It will be important for the community to report new findings using this probe to fully validate its applicability.

Aug 18 2017 - 4:24pm

A 2020 publication shows that T0901317 exert unspecific effects on pancreatic β-cell function DOI: 10.1007/s12020-020-02241-4

Jul 9 2020 - 1:27pm

GW3965

Probe Information

Target Details

NR1H2, LXR-b, LXRB, NER, NER-I, RIP15, UNR, NR1H3, LXR-a, LXRA, RLD-1

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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GW3965

Probe Information

Target Details

NR1H2, LXR-b, LXRB, NER, NER-I, RIP15, UNR, NR1H3, LXR-a, LXRA, RLD-1

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?