GSK2033

Protein target name:

LXR-alpha, LXR-beta

Mechanism of action:

AntagonistInverse Agonistmix Agonist/Antagonist in vivo

Recommended Concentration for use in cells:

>100 nM

Probe Availability

MedchemExpress

TOCRIS

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:

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

Probe Details

Chemical Probes Portal ID:

CPP1776

Probe alias:

Compound 17

PubChem CID:

46203250

ChEMBL ID:

CHEMBL1093266

SMILES string:

CC1=CC(=C(C(=C1)C)S(=O)(=O)N(CC2=CC=C(C=C2)C3=CC(=CC=C3)S(=O)(=O)C)CC4=CC=C(O4)C(F)(F)F)C

InChi Key:

PSOXOVKYGWBTPB-UHFFFAOYSA-N

Orthogonal probe:

TO901317

PAINs evaluation:

PAINS Free

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H), 2.55 (s, 6 H), 3.29 (s, 3 H), 4.34 (s, 2 H), 4.41 (s, 2 H), 6.39 (d, J=3.48 Hz, 1 H), 7.03 (d, J=2.09 Hz, 1 H), 7.07 (s, 2 H), 7.29 (d, J=8.00 Hz, 2 H), 7.61 - 7.82 (m, 3 H), 7.91 (d, J=8.00 Hz, 1 H), 8.01 (d, J=8.00 Hz, 1 H), 8.13 (s, 1 H);

13C NMR (CDCl3) δ 20.1, 22.8, 41.2, 44.6, 50.0, 110.2, 112.4 (JCF = 2.8 Hz), 117.5, 120.2, 125.8, 126.1, 127.5, 129.5, 129.9, 132.1, 132.2, 132.6, 135.6, 138.7, 140.4, 141.3, 142.1, 143.1, 152.8;

19F NMR (CDCl3) δ -64.7

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

pIC50

7.5

Potency assay:

LXR LEADseeker binding assay

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

3L0E

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

IC50

17 and 52 nM LXRa9 and 10 nM LXRb

Potency assay (cells):

Co-transfection using Luciferase reporter assay, basal gene expression suppression for ABCA1 and SREBP-1c genes

Off target activity in cells

Selectivity against nonfamily targets (cells):

GSK2033 was inactive (XC50 > 10 μM) in cellular and biochemical NR assays, including PXR, LRH-1, and FXR.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

no evidence of cell toxicity

In vivo validation

Organism:

C57BL6 DIO mice

Dose:

30 mg/Kg40 mg/Kg50 mg/Kg

Route of delivery:

Intraperitoneal

Plasma half life:

8 h

Systemic clearance:

Clint > 1.0 mL/min/mg pro

Organ of Interest

Organ (O):

Liver

Target engagement assay:

Gal4-LBD cotransfection assay: GSK2033 activated several nuclear receptors including RORγ, FXR, VDR, PXR, CAR, ERα, ERβ, GR, ERRβ, and ERRγ while suppressing the activity of ERRα and PR.

Primary Reference

Reference (doi):

10.1021/jm901797p

Reference (PMID):

20345102 27680310

GSK2033

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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GSK2033

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?