Target Information
| Target General Information | Top | |||||
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| Target ID |
T46456
(Former ID: TTDR01075)
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| Target Name |
Retinoic acid receptor RXR-gamma (RXRG)
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| Synonyms |
Retinoid X receptor gamma; Nuclear receptor subfamily 2 group B member 3; NR2B3
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| Gene Name |
RXRG
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Kaposi sarcoma [ICD-11: 2B57] | |||||
| 2 | Light sensitivity impairment [ICD-11: 9D45] | |||||
| Function |
Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. Receptor for retinoic acid.
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MYGNYSHFMKFPAGYGGSPGHTGSTSMSPSAALSTGKPMDSHPSYTDTPVSAPRTLSAVG
TPLNALGSPYRVITSAMGPPSGALAAPPGINLVAPPSSQLNVVNSVSSSEDIKPLPGLPG IGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLIYTCRDNKD CLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECATSGHEDMPVERIL EAELAVEPKTESYGDMNMENSTNDPVTNICHAADKQLFTLVEWAKRIPHFSDLTLEDQVI LLRAGWNELLIASFSHRSVSVQDGILLATGLHVHRSSAHSAGVGSIFDRVLTELVSKMKD MQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTKQKYPEQPGRFAKLL LRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLETPLQIT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Alitretinoin | Drug Info | Approved | Kaposi sarcoma | [2], [3] | |
| 2 | Vitamin A | Drug Info | Approved | Night blindness | [1], [4] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | NRX-4204 | Drug Info | Phase 2 | Diabetic complication | [5], [6] | |
| 2 | 9cUAB-30 | Drug Info | Phase 1 | Solid tumour/cancer | [7] | |
| 3 | IRX4204 | Drug Info | Phase 1 | Prostate cancer | [8] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | SR-11237 | Drug Info | Terminated | Solid tumour/cancer | [9], [10] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | Alitretinoin | Drug Info | [11] | |||
| Binder | [+] 1 Binder drugs | + | ||||
| 1 | Vitamin A | Drug Info | [1] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | NRX-4204 | Drug Info | [12] | |||
| 2 | 9cUAB-30 | Drug Info | [7] | |||
| 3 | IRX4204 | Drug Info | [13] | |||
| 4 | SR-11237 | Drug Info | [14] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | AGN-34 | Drug Info | [15] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | LG100754 | Drug Info | [16] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| PPAR signaling pathway | hsa03320 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Th17 cell differentiation | hsa04659 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Thyroid hormone signaling pathway | hsa04919 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Adipocytokine signaling pathway | hsa04920 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Parathyroid hormone synthesis, secretion and action | hsa04928 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 1.20E-05 |
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| Closeness centrality | 2.09E-01 | Radiality | 1.37E+01 | Clustering coefficient | 1.43E-01 |
| Neighborhood connectivity | 1.88E+01 | Topological coefficient | 2.09E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 8 KEGG Pathways | + | ||||
| 1 | PPAR signaling pathway | |||||
| 2 | Thyroid hormone signaling pathway | |||||
| 3 | Adipocytokine signaling pathway | |||||
| 4 | Pathways in cancer | |||||
| 5 | Transcriptional misregulation in cancer | |||||
| 6 | Thyroid cancer | |||||
| 7 | Small cell lung cancer | |||||
| 8 | Non-small cell lung cancer | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | Regulation of Androgen receptor activity | |||||
| 2 | RXR and RAR heterodimerization with other nuclear receptor | |||||
| 3 | Retinoic acid receptors-mediated signaling | |||||
| 4 | a6b1 and a6b4 Integrin signaling | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Nuclear Receptor transcription pathway | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Vitamin A and Carotenoid Metabolism | |||||
| 2 | Adipogenesis | |||||
| 3 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Vitamins and cofactors: highlights of ESBOC 2009. Nat Chem Biol. 2009 Aug;5(8):530-3. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2645). | |||||
| REF 3 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4053). | |||||
| REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2811). | |||||
| REF 6 | ClinicalTrials.gov (NCT01540071) Trial of NRX 194204 in Castration- and Taxane-Resistant Prostate Cancer. U.S. National Institutes of Health. | |||||
| REF 7 | In vitro metabolic characterization, phenotyping, and kinetic studies of 9cUAB30, a retinoid X receptor-specific retinoid. Drug Metab Dispos. 2007 Jul;35(7):1157-64. | |||||
| REF 8 | ClinicalTrials.gov (NCT02438215) Study of IRX4204 for Treatment of Early Parkinson's Disease. U.S. National Institutes of Health. | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2809). | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005745) | |||||
| REF 11 | Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4. | |||||
| REF 12 | DOI: 10.1038/scibx.2010.766 | |||||
| REF 13 | Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.Oncotarget.2016 Feb 16;7(7):7469-79. | |||||
| REF 14 | Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology. ChemMedChem. 2009 Jul;4(7):1143-52. | |||||
| REF 15 | Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005 Aug 25;48(17):5383-403. | |||||
| REF 16 | Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature. 1996 Oct 3;383(6599):450-3. | |||||
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