LXR-623

Protein target name:

NR1H3, NR1H2

Mechanism of action:

Partial Agonist

Recommended Concentration for use in cells:

up to 2 uM

Probe Availability

MedChemExpress

TOCRIS

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Hormone Nuclear Receptor

Subclass:

NR1 Subfamily

HUGO ID:

HGNC:7965 HGNC:7966

Entrez gene ID:

7376 10062

UNIPROT ID:

P55055 Q13133

Target alias:

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

Probe Details

Chemical Probes Portal ID:

CPP1856

Probe alias:

LXR623, WAY-252623

PubChem CID:

16734800

ChEMBL ID:

CHEMBL456237

SMILES string:

C1=CC2=C(N(N=C2C(=C1)C(F)(F)F)CC3=C(C=C(C=C3)F)Cl)C4=CC=C(C=C4)F

InChi Key:

KYWWJENKIMRJBI-UHFFFAOYSA-N

Orthogonal probe:

TO901317GSK2033SR9238

Physico-chemical properties

NMR:

1H NMR (DMSO-d6, 400 MHz) δ 5.77 (s, 2H), 6.92 (m, 1H), 7.14 (dt, 1H), 7.24 (t, 1H, J = 7.8 Hz), 7.43 (m, 3H), 7.65 (m, 2H), 7.76 (d, 1H, J = 7.01 Hz), 7.83 (d, 1H, J = 8.45 Hz);

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

LXRβ 24 nM, LXRα 179 nM

Potency assay:

Radio Labelled binding assay

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

not publ.

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

EC50 (% effect)

GAL4 LXRβ 3.67 uM (73), GAL4 LXRα 6.66 uM (53), ABAC1 0.53 uM (100), C-Efflux 1.27 uM (140), SREBP1 2.11 uM (58), Lipid acc. 1.91 uM (35)

Potency assay (cells):

Huh-7 human hepatoma cell based Gal4 LXRα or LXRβ transactivation assay, Cell functional assay for gene expression.

Target engagement assay (cells):

Several candidate biomarkers of LXR agonist exposure and activity have been identified in peripheral blood, and two of these (ABCA1 and ABCG1) have been demonstrated to change substantially (up to 200 fold change) and rapidly (≤ 4 hours) upon compound treatment.

Off target activity in cells

Probe Selectivity in Cell:

PPAR and FXR Gal4 transactivation assays show no agonist effects for PPARα, PPARγ, PPARδ and FXR. Binding Assays: PXR 1.77 uM, RXR >10 uM, GR 1.0 uM, MR no binding, AR2.3 uM, PR >1 uM, ERα No binding, ERβ No binding, TRα No binding, TRβ No binding

In vivo validation

Organism:

C57/Bl6 miceMale Long Evans ratsMale Golden Syrian hamstersCynomolgus monkeysNew Zealand White Rabbit

Dose:

30 (r), 50 (m) mg/kg/day, 15, 50 mg/Kg (R)20, 60, and 120 mg/kg/day (ham), 50 mg/Kg (mon)Rab

Route of delivery:

Oral

Cmax:

2200 ng/mL (15mg/Kg)3758 ng/mL (50 mg/Kg)

Tmax:

6 hƒrabb

Organ of Interest

Organ (O):

LiverBrain

Primary Reference

Reference (doi):

10.1186/1479-5876-6-59 10.1194/jlr.M900037-JLR200 10.1093/eurheartj/ehr136 10.1016/j.ccell.2016.09.008 10.1021/jm800799q

Reference (PMID):

18925943 19318684 21606082 27746144 18973288

LXR-623

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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LXR-623

Probe Availability

Probe Information

Target Details

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

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?