Top ▲
target has curated data in GtoImmuPdb
Target id: 600
Nomenclature: RAR-related orphan receptor-γ
Systematic Nomenclature: NR1F3
Gene and Protein Information  |
|||||
| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 518 | 1q21 | RORC | RAR related orphan receptor C | 12 |
| Mouse | 516 | 3 F2.1 | Rorc | RAR-related orphan receptor gamma | 25 |
| Rat | - | 2q34 | Rorc | RAR-related orphan receptor C | |
| Gene and Protein Information Comments | |||||
| Two protein isoforms, produced by alternative promoter usage, are expressed from the human RORC gene. Isoform 1 (RORC1) is the 518 amino acid full-length product. Isoform 2 (RORC2 or RORγt) is shorter, missing the first 21 amino acids of isoform 1 and having amino acids 22-24 (HTS) replaced by MRT. Isoform 2 is exclusively expressed by immature thymocytes. | |||||
| Previous and Unofficial Names |
| nuclear receptor ROR-gamma | nuclear receptor RZR-gamma | RORC2 | RORγ | RORγt | RZRγ | Thor | thymus orphan receptor | TOR |
| Database Links |
|
| Alphafold | P51449 (Hs), P51450 (Mm) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1741186 (Hs), CHEMBL1293231 (Mm) |
| Ensembl Gene | ENSG00000143365 (Hs), ENSMUSG00000028150 (Mm), ENSRNOG00000020836 (Rn) |
| Entrez Gene | 6097 (Hs), 19885 (Mm), 368158 (Rn) |
| Human Protein Atlas | ENSG00000143365 (Hs) |
| KEGG Gene | hsa:6097 (Hs), mmu:19885 (Mm), rno:368158 (Rn) |
| OMIM | 602943 (Hs) |
| Pharos | P51449 (Hs) |
| RefSeq Nucleotide | NM_001001523 (Hs), NM_005060 (Hs), NM_011281 (Mm) |
| RefSeq Protein | NP_001001523 (Hs), NP_005051 (Hs), NP_035411 (Mm) |
| SynPHARM |
6597 (in complex with 25-hydroxycholesterol) 84981 (in complex with TAK-828F) |
| UniProtKB | P51449 (Hs), P51450 (Mm) |
| Wikipedia | RORC (Hs) |
| Selected 3D Structures |
|||||||||||||
|
|
||||||||||||
| Natural/Endogenous Ligands |
| 25-hydroxycholesterol |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Even although no ligands have been identified, hydroxycholesterols have been shown to promote the recruitment of coactivators by RORγ using biochemical assays [15]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists |
|||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Both ALRT 1550 and all-trans retinoic acid partially inhibit RORγ transcriptional activity. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| RORγ is a nuclear receptor transcription factor that acts as an immune cell master control switch (most likely associated with expression of the RORγt isoform). This receptor is an essential regulator of type 17 effector T cell differentiation and function. RORγt inhibitors (antagonists and inverse agonists) [3,10,24,31] are in development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis [2,14]. Inverse agonists block RORγt-driven development and differentiation of IL-17 producing Th17 cells to reduce inflammation. Examples include AZD0284 (see the ACS webinar Psoriasis: Treatment and Novel Approaches) and GNE-3500 [8]. Development of VTP-43742 [10], Allergan's RORγ inverse agonist, was terminated in early 2018 due to safety issues detected in their Phase 2 psoriasis trial. As immuno-oncology candidates, RORγ agonists are being studied for their potential to improve immune detection/destruction of cancer cells [13]. For example, Lycera's orally active agent cintirorgon is being evaluated in early phase clinical trial NCT02929862 in patients with locally advanced or metastatic solid tumours. |
| Immuno Process Associations | ||
|
||
|
||
|
||
|
||
|
||
|
||
|
| DNA Binding |
|||||||
|
|||||||
| DNA Binding Comments | |||||||
| It has been shown that mouse RORγ does not recognise the classical ROREs but binds with high affinity as a homodimer to DR4 and DR5 elements. | |||||||
| Co-binding Partners |
|||
| Name | Interaction | Effect | Reference |
| Mi-2beta | Physical, Functional | Mi-2beta: A yeast two-hybrid screen with Y190 yeast cells under stringent conditions resulted in the identification of CHD4, also known as Mi-2beta, as a RORgamma-interacting protein. This interaction was confirmed by GST pull-down assays. This interaction occurred within the middle regulatory region (amino acids 719-1164) of Mi-2beta. Transfection of Gal4-RORgamma into HeLa cells resulted in constitutive transactivation of the MH100-tk-luc reporter. The addition of Mi-2beta resulted in a dramatic 50% decrease in Gal4-RORgamma-mediated transactivation. These data demonstrate that RORgamma forms a protein-protein interaction with the regulatory region of Mi-2beta, resulting in inhibition of RORgamma transcriptional activity. | 16 |
| Main Co-regulators |
||||||
| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOA1 | Co-activator | No | No | Yes | 20 | |
| HR | Co-repressor | No | Yes | Yes | 22 | |
| Tissue Distribution
|
||||||||||
|
||||||||||
| Tissue Distribution Comments | ||||||||||
| In the human tissues RORγ was shown to be highly expressed as a 3.2 kb mRNA. In thymus, two other transcripts at 7.2 and 5.2 kb were also detected. In mouse, other authors found a predominant expression in thymus as in other tissues such as liver, heart, tongue, muscle, and diaphragm. Notably, no expression was found in spleen, or bone marrow. The major transcript is found at 2.5 kb but a 3.5 kb form is detected in several organs such as thymus. The same study reports expression in a number of mammalian cell lines. Recently, it has been shown that during fetal life, the nuclear hormone receptor RORγt is expressed exclusively in and is required for the generation of lymphoid tissue inducer cells [6,33]. | ||||||||||
| Physiological Consequences of Altering Gene Expression
|
||||||||||
|
| Phenotypes, Alleles and Disease Models
|
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biologically Significant Variants
|
||||||||||||||
|
1. Aicher TD, Taylor CB, Vanhuis CA. (2016) Aryl dihydro-2h-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of rory and the treatment of disease. Patent number: WO2016201225A1. Assignee: Lycera Corporation. Priority date: 11/06/2015. Publication date: 15/12/2016.
2. Bronner SM, Zbieg JR, Crawford JJ. (2017) RORγ antagonists and inverse agonists: a patent review. Expert Opin Ther Pat, 27 (1): 101-112. [PMID:27629281]
3. Dai J, Choo MK, Park JM, Fisher DE. (2017) Topical ROR Inverse Agonists Suppress Inflammation in Mouse Models of Atopic Dermatitis and Acute Irritant Dermatitis. J Invest Dermatol, 137 (12): 2523-2531. [PMID:28774591]
4. Duan J, Dhar TGM, Marcoux D, Shi Q, Batt DG, Liu Q, Cherney RJ, Cornelius AMC, Srivastava AS, Bertrand MB et al.. (2016) Tricyclic sulfones as rorϒ modulators. Patent number: WO2016179460A1. Assignee: Bristol-Myers Squibb. Priority date: 07/05/2015. Publication date: 10/11/2016.
5. Eberl G, Littman DR. (2003) The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol Rev, 195: 81-90. [PMID:12969312]
6. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. (2004) An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol, 5 (1): 64-73. [PMID:14691482]
7. Fauber BP, Gobbi A, Robarge K, Zhou A, Barnard A, Cao J, Deng Y, Eidenschenk C, Everett C, Ganguli A et al.. (2015) Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorg Med Chem Lett, 25 (15): 2907-12. [PMID:26048793]
8. Fauber BP, René O, Deng Y, DeVoss J, Eidenschenk C, Everett C, Ganguli A, Gobbi A, Hawkins J, Johnson AR et al.. (2015) Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist. J Med Chem, 58 (13): 5308-22. [PMID:26061388]
9. Flick AC, Jones P, Kaila N, Mente SR, Schnute ME, Trzupek JD, Vazquez ML, Xing L, Zhang L, Wennerstal GM et al.. (2016) Methyl-and trifluoromethyl-substituted pyrrolopyridine modulators of rorc2 and methods of use thereof. Patent number: WO2016046755A1. Assignee: Pfizer Inc.. Priority date: 26/09/2014. Publication date: 31/03/2016.
10. Gege C. (2016) Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742. Expert Opin Ther Pat, 26 (6): 737-44. [PMID:26895086]
11. He YW, Deftos ML, Ojala EW, Bevan MJ. (1998) RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity, 9 (6): 797-806. [PMID:9881970]
12. Hirose T, Smith RJ, Jetten AM. (1994) ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun, 205 (3): 1976-83. [PMID:7811290]
13. Hu X, Liu X, Moisan J, Wang Y, Lesch CA, Spooner C, Morgan RW, Zawidzka EM, Mertz D, Bousley D et al.. (2016) Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity. Oncoimmunology, 5 (12): e1254854. [PMID:28123897]
14. Huang Z, Xie H, Wang R, Sun Z. (2007) Retinoid-related orphan receptor gamma t is a potential therapeutic target for controlling inflammatory autoimmunity. Expert Opin Ther Targets, 11 (6): 737-43. [PMID:17504012]
15. Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y. (2010) Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol, 24 (5): 923-9. [PMID:20203100]
16. Johnson DR, Lovett JM, Hirsch M, Xia F, Chen JD. (2004) NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem Biophys Res Commun, 318 (3): 714-8. [PMID:15144897]
17. Kono M, Ochida A, Oda T, Imada T, Banno Y, Taya N, Masada S, Kawamoto T, Yonemori K, Nara Y et al.. (2018) Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist. J Med Chem, 61 (7): 2973-2988. [PMID:29510038]
18. Kumar N, Lyda B, Chang MR, Lauer JL, Solt LA, Burris TP, Kamenecka TM, Griffin PR. (2012) Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol, 7 (4): 672-7. [PMID:22292739]
19. Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Busby SA, Garcia-Ordonez RD, Burris TP, Griffin PR. (2010) The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol Pharmacol, 77 (2): 228-36. [PMID:19887649]
20. Kurebayashi S, Nakajima T, Kim SC, Chang CY, McDonnell DP, Renaud JP, Jetten AM. (2004) Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma. Biochem Biophys Res Commun, 315 (4): 919-27. [PMID:14985100]
21. Marcoux D, Duan JJ, Shi Q, Cherney RJ, Srivastava AS, Cornelius L, Batt DG, Liu Q, Beaudoin-Bertrand M, Weigelt CA et al.. (2019) Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy. J Med Chem, 62 (21): 9931-9946. [PMID:31638797]
22. Moraitis AN, Giguère V, Thompson CC. (2002) Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol Cell Biol, 22 (19): 6831-41. [PMID:12215540]
23. Narjes F, Llinas A, von Berg S, Jirholt J, Lever S, Pehrson R, Collins M, Malmberg M, Svanberg P, Xue Y et al.. (2021) AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2. Journal of Medicinal Chemistry, Online ahead of print. DOI: 10.1021/acs.jmedchem.1c01197 [PMID:34464130]
24. Noguchi M, Nomura A, Murase K, Doi S, Yamaguchi K, Hirata K, Shiozaki M, Hirashima S, Kotoku M, Yamaguchi T et al.. (2017) Ternary complex of human RORγ ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment. Genes Cells, 22 (6): 535-551. [PMID:28493531]
25. Ortiz MA, Piedrafita FJ, Pfahl M, Maki R. (1995) TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol Endocrinol, 9 (12): 1679-91. [PMID:8614404]
26. Schnute ME, Trujillo JI, Lee KL, Unwalla R, Vajdos FF, Kauppi B, Nuhant P, Flick AC, Crouse KK, Zhao Y et al.. (2023) Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists. ACS Medicinal Chemistry Letters, Online ahead of print. DOI: 10.1021/acsmedchemlett.2c00500
27. Schnute ME, Wennerstål M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers N et al.. (2018) Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist. J Med Chem, 61 (23): 10415-10439. [PMID:30130103]
28. Smith SH, Peredo CE, Takeda Y, Bui T, Neil J, Rickard D, Millerman E, Therrien JP, Nicodeme E, Brusq JM et al.. (2016) Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PLoS ONE, 11 (2): e0147979. [PMID:26870941]
29. Solt LA, Kumar N, He Y, Kamenecka TM, Griffin PR, Burris TP. (2012) Identification of a selective RORγ ligand that suppresses T(H)17 cells and stimulates T regulatory cells. ACS Chem Biol, 7 (9): 1515-9. [PMID:22769242]
30. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidović D et al.. (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, 472 (7344): 491-4. [PMID:21499262]
31. Song Y, Xue X, Wu X, Wang R, Xing Y, Yan W, Zhou Y, Qian CN, Zhang Y, Xu Y. (2016) Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse agonists: Virtual screening, structure-based optimization, and biological evaluation. Eur J Med Chem, 116: 13-26. [PMID:27043267]
32. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R. (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol, 10 (10): 820-5. [PMID:12958591]
33. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR. (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science, 288 (5475): 2369-73. [PMID:10875923]
34. Zhang H, Lapointe BT, Anthony N, Azevedo R, Cals J, Correll CC, Daniels M, Deshmukh S, van Eenenaam H, Ferguson H et al.. (2020) Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases. ACS Med Chem Lett, 11 (2): 114-119. DOI: 10.1021/acsmedchemlett.9b00431 [PMID:32071676]
35. Zhang Y, Wu X, Xue X, Li C, Wang J, Wang R, Zhang C, Wang C, Shi Y, Zou L et al.. (2019) Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. J Med Chem, 62 (9): 4716-4730. [PMID:30964293]
