Orphan Nuclear Receptor

Nuclear receptors consist of 48 transcription factors in humans. Of these, 10 are considered orphan nuclear receptors (ONRs) because the natural ligand has not yet been identified, while 26 are former orphans but are now labeled as adopted NRs after the discovery of their respective natural ligands. Although adopted NRs bind endogenous ligands, it remains unclear whether the NR function is ligand-regulated. The remaining 12 NRs employ endocrine hormones as endogenous ligands and are classified as endocrine NRs. Ligand binding to NRs typically induce a conformational change that enable binding of NRs to target DNA motifs across the genome called nuclear receptor response elements (NRREs) and recruitment of co-regulator proteins that modulate transcription of target genes. Because ONRs could potentially be ligand-regulated or druggable, they are attractive therapeutic targets using small molecule compounds. Orphan nuclear receptors provide a unique resource for uncovering novel regulatory systems that impact human health and also provide drug targets for a variety of human diseases. Ligands of nuclear receptors have been used in several important therapeutic areas, such as breast cancers, skin disorders and diabetes^[1]^[2].

References:

[1]. Vera IMS. Advances in Orphan Nuclear Receptor Pharmacology: A New Era in Drug Discovery. ACS Pharmacol Transl Sci. 2018 Sep 14;1(2):134-137. [Content Brief]

[2]. Shi Y. Orphan nuclear receptors in drug discovery. Drug Discov Today. 2007 Jun;12(11-12):440-5. [Content Brief]

Orphan Nuclear Receptor Related Products (29):

By Effects:	Inhibitors (8) Agonists (8) Antagonists (5) Modulators (4)

Cat. No.	Product Name	Effect	Purity	Chemical Structure

HY-B1058

Benfluorex hydrochloride	Agonist	99.85%
Benfluorex hydrochloride (JP-992 hydrochloride) is a hepatic nuclear factor 4 alpha (HNF4α) activator.

HY-108469

BI-6015	Antagonist	99.90%
BI-6015 is a hepatocyte nuclear factor 4α (HNF4α) antagonist that can inhibit the expression of known HNF4α target genes. BI6015 represses insulin promoter activity through HNF4α antagonism. BI-6015 can be used for the research of cancer and diabetes.

HY-115613

ML-180	Inhibitor	99.96%
ML-180 (SR1848) is a potent orphan nuclear receptor *liver receptor homolog 1 (LRH-1; NR5A2)* inverse agonist with an IC₅₀ of 3.7 μM. ML-180 is inactive for steroidogenic factor-1 (SF-1; NR5A1; IC₅₀>10 μM). ML-180 has the potential for LRH-1-dependent cancers.

HY-156190A

NR2F2-IN-1 free base	Inhibitor	99.34%
NR2F2-IN-1 (free base) is a potent and selective orphan nuclear receptor COUP-TFII (NR2F2) inhibitor. NR2F2-IN-1 (free base) substantially inhibits COUP-TFII–driven NGFIA reporter expression. NR2F2-IN-1 (free base) directly binds to the COUP-TFII ligand-binding domain and disrupts COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation.

HY-149913

NR2F1 agonist 1	Antagonist	99.06%
NR2F1 agonist 1, a nuclear receptor NR2F1 agonist, specifically activates dormancy programs in malignant cells. NR2F1 agonist 1 up-regulates NR2F1 and downstream target genes that regulate dormancy. NR2F1 agonist 1 induces neural crest-like and growth suppression in head and neck squamous cell carcinoma (HNSCC) via NR2F1 activation. NR2F1 agonist 1 inhibits tumor growth in a mouse primary tumor model.

HY-176847

HNF4A-IN-1	Inhibitor
HNF4A-IN-1 (Compound 17) is a Hepatocyte nuclear factor 4 alpha (HNF4A) inhibitor. HNF4A-IN-1 has potent anticancer activity against human head and neck squamous cells (SCC131 cells) and with no toxicity to normal cells. HNF4A-IN-1 significantly inhibits SCC131 cells growth with an IC₅₀ of 1.75 μM, and induces apoptosis and G2/M cell cycle arrest. HNF4A-IN-1 promotes tumor regression in SCC131 tumor xenografts mouse models.

HY-173340

LRH-1 agonist-1
LRH-1 agonist-1 (compound 74) is an agonist of LRH-1 with IC₅₀ value of 47 μM.

HY-131445B

RR-RJW100		99.73%
RR-RJW100, the enantiomer of RJW100, is an nuclear receptor liver receptor homolog 1 (LRH-1) and steroidogenic factor 1 (SF-1) agonist. RJW100 can be synthesized as two enantiomers, RR-RJW100 and SS-RJW100, with RR-RJW100 shown to be the more potent LRH-1 agonist. RR-RJW100 is involved in the regulation of metabolic homeostasis and is used in studies of diabetes, liver disease and inflammatory bowel disease.

HY-107404

SID 7969543	Inhibitor	99.42%
SID 7969543 is a selective SF-1 (steroidogenic factor 1, NR5A1) inhibitor with an IC₅₀ of 760 nM. SID 7969543 inhibits SF-1-triggered luciferase expression with IC₅₀ of 30 nM. SF-1 is a transcription factor belonging to the nuclear receptor superfamily.

HY-147105

LRH-1 modulator-1	Modulator	98.04%
LRH-1 modulator-1 (compound 6N) is a potent LRH-1 (liver receptor homolog-1) modulator/agonist. LRH-1 modulator-1 shows anti-inflammatory effects in intestinal organoids. LRH-1 modulator-1 induces anti-inflammatory cytokine IL-10, and reduces inflammatory cytokine IL-1b and TNFa.

HY-135589

7-[4-(2-Piperidinyl)ethoxy]benzoyl Raloxifene	Antagonist	98.52%
7-[4-(2-Piperidinyl)ethoxy]benzoyl Raloxifene is a liver receptor homolog-1 (LRH-1) antagonist with an IC₅₀ of 3.1 μM.

HY-135572

TLX agonist 1	Modulator	99.94%
TLX agonist 1 (ccrp2) is an orphan nuclear receptor tailless (TLX, NR2E1) modulator (EC₅₀=1μM; K_d= 650 nM). TLX agonist 1 potentiates TLX transcriptional repressive activity.

HY-128207

SID7970631	Inhibitor	98.30%
SID7970631, as an isoquinolinone analog, is a potent and selective submicromolar SF-1 inhibitor (IC₅₀=255 nM). SID7970631 can be used for the research of cancer.

HY-161115

NR2E3 agonist 1	Agonist	99.48%
NR2E3 agonist 1 (Compound 11a) is a small molecule agonist of the photoreceptor-specific nuclear receptor (NR2E3) with an EC₅₀ value of less than 200 nM. NR2E3 agonist 1 can be used in retinitis pigmentosa research.

HY-131445A

SS-RJW100		99.91%
SS-RJW100 is a enantiomer of RJW100, which is a racemic agonist of nuclear receptor liver receptor homolog 1 (LRH-1) and steroidogenic factor 1 (SF-1). SS-RJW100 promotes recruitment of coregulator protein fragments in vitro, recruits the transcriptional intermediary factor 2 (Tif2) coactivator to LRH-1. SS-RJW100 diminishes LRH-1 allosteric activation networks, shows poor thermal stability.

HY-147105A

(+)-LRH-1 modulator-1	Modulator	99.38%
(+)-LRH-1 modulator-1 is a stereoisomer of LRH-1 modulator-1. LRH-1 modulator-1 (compound 6N) is a potent LRH-1 (liver receptor homolog-1) modulator/agonist. LRH-1 modulator-1 has anti-inflammatory effects in intestinal organoids. LRH-1 modulator-1 induces the anti-inflammatory cytokine IL-10 and reduces the inflammatory cytokines IL-1b and TNFa.

HY-148608

LysoPalloT-NH-amide-C3-ph-m-O-C11	Agonist
LysoPalloT-NH-amide-C3-ph-m-O-C11 is an agonist for GPR174 with an EC₅₀ of 34 nM.

HY-156190

NR2F2-IN-1	Inhibitor
NR2F6 modulator-2 (CIA1) is a potent and selective orphan nuclear receptor COUP-TFII (NR2F2) inhibitor. NR2F6 modulator-2 substantially inhibits COUP-TFII–driven NGFIA reporter expression. NR2F6 modulator-2 directly binds to the COUP-TFII ligand-binding domain and disrupts COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation.

HY-159920

PSB-22269	Antagonist
PSB-22269 is a GPR17 antagonist with a K_i value of 8.91 nM. PSB-22269 further demonstrated significant inhibitory effects in cAMP and G protein activation assays. Molecular docking studies revealed that the binding site of PSB-22269 contains positively charged arginine residues and a hydrophobic pocket. PSB-22269 provides a strategy to promote remyelination and holds promise for research in the field of multiple sclerosis.

HY-109869

Photoregulin1
Photoregulin1 is a compound with the potential to inhibit retinitis pigmentosa that modulates gene expression in retinal cells and slows the degeneration of photoreceptors in a mouse model.

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