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 (40):

By Effects:	Inhibitors (11) Agonists (12) Antagonists (8) Activator (1) 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	99.31%
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-134462A

RJW103 TFA	Agonist
RJW103 TFA is an acid-stable SF-1 (NR5A1) and LRH-1 agonist with pEC₅₀ values of 6.5 and 5.9, respectively. RJW103 TFA activates SF-1- and LRH-1-mediated transcription of endogenous target genes. RJW103 TFA can be used in research on cancer, endocrinology and metabolic diseases, such as adrenocortical tumors.

HY-18314B

(Z)-GW 441756	Activator
(Z)-GW 441756 is a hepatocyte nuclear factor 4α (HNF4α) activator, with an EC₅₀ of 9.2 μM and a K_a of 4.6 μM in human systems. (Z)-GW 441756 directly interacts with the ligand-binding domain of HNF4α via persistent hydrogen bonds and hydrophobic interactions within the binding pocket. (Z)-GW 441756 reduces the accumulation of triglycerides and total cholesterol. (Z)-GW 441756 inhibits ferroptosis through a non-antioxidant mechanism. (Z)-GW 441756 decreases plasma triglyceride and total cholesterol levels in animal models of hyperlipidemia. (Z)-GW 441756 can be used in studies related to hyperlipidemia.

HY-180403

TLX agonist 3	Agonist
TLX agonist 3 is a potent and selective tailless homolog (TLX, NR2E1) agonist with an EC₅₀ of 0.25 μM and a K_d of 1.6 μM). TLX agonist 3 shows high selectivity over related nuclear receptors, and promotes TLX oligomerization with an EC₅₀ of 5.0 μM. TLX agonist 3 can be used for the research of neurodegenerative diseases.

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-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-147105

LRH-1 agonist-2	Agonist	98.58%
LRH-1 agonist-2 (Compound 6N) is a selective, full LRH-1 agonist with an EC₅₀ of 15.7 nM. LRH-1 agonist-2 directly interacts with the Thr352 and His390 residues in the LRH-1 binding pocket, promotes allosteric signaling to the activation function surface (AFS), stabilizes the AFS and enhances coactivator recruitment. LRH-1 agonist-2 induces the anti-inflammatory cytokine IL-10, and reduces the pro-inflammatory cytokines IL-1β and TNFα. LRH-1 modulator-1 exerts anti-inflammatory effects in intestinal organoids. LRH-1 modulator-1 can be used in studies related to inflammatory bowel disease.

HY-176136

HNF4 agonist 1	Agonist	99.37%
HNF4 agonist 1 is a HNF4 agonist. HNF4 agonist 1 activates HNF4α and HNF4γ with EC₅₀ values of 6 nM and 17 nM, respectively. HNF4 agonist 1 can be used in studies related to maturity-onset diabetes of the young type 1 (mody-1).

HY-135589

7-[4-(2-Piperidinyl)ethoxy]benzoyl Raloxifene	Antagonist	98.67%
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-176847

DHQZ-17	Inhibitor	99.58%
DHQZ-17 is a HNF4A inhibitor. DHQZ-17 triggers apoptosis in head and neck squamous cell carcinoma cells. DHQZ-17 can be used for the research of head & neck squamous cell carcinoma.

HY-134462

RJW103	Agonist	98.71%
RJW103 is an acid-stable SF-1 (NR5A1) and LRH-1 agonist with pEC₅₀ values of 6.5 and 5.9, respectively. RJW103 activates SF-1- and LRH-1-mediated transcription of endogenous target genes. RJW103 can be used in research on cancer, endocrinology and metabolic diseases, such as adrenocortical tumors.

HY-118054

LRH-1 Inhibitor-3	Inhibitor	99.9%
LRH-1 Inhibitor-3 is a small molecule that inhibits LRH-1 transcriptional activity, thereby decreasing the expression of target genes associated with cell growth and proliferation. LRH-1 Inhibitor-3 has shown potential in reducing cancer cell proliferation in human pancreatic, colon, and breast adenocarcinoma cell lines. LRH-1 Inhibitor-3 serves as a molecular probe for investigating the role of LRH-1 in various malignancies.

HY-W649594

NR2F6 modulator-2	Modulator	99.46%
NR2F6 modulator-2 (Compound I) is an autorepressed orphan nuclear receptor NR2F6 (Nuclear Receptor subfamily 2 group F member 6) modulator. NR2F6 modulator-2 can inhibits the recruitment of the bio-NSD1 peptide with an IC₅₀ of 2.0 equivalents of NR2F6. NR2F6 modulator-2 can be used for the researches of cancer and immunology.

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.

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