Target Information
Target General Information | Top | |||||
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Target ID |
T25307
(Former ID: TTDI03508)
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Target Name |
Nuclear receptor ROR-gamma (RORG)
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Synonyms |
Retinoid-related orphan receptor-gamma; RZRG; RORG; RAR-related orphan receptor C; Nuclear receptor subfamily 1 group F member 3; Nuclear receptor RZR-gamma; NR1F3
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Gene Name |
RORC
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 6 Target-related Diseases | + | ||||
1 | Lung cancer [ICD-11: 2C25] | |||||
2 | Psoriasis [ICD-11: EA90] | |||||
3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
4 | Autoimmune disease [ICD-11: 4A40-4A45] | |||||
5 | Crohn disease [ICD-11: DD70] | |||||
6 | Multiple sclerosis [ICD-11: 8A40] | |||||
Function |
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1. Regulates the rhythmic expression of PROX1 and promotes its nuclear localization. Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity.
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BioChemical Class |
Nuclear hormone receptor
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UniProt ID | ||||||
Sequence |
MDRAPQRQHRASRELLAAKKTHTSQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRSQR
CNAAYSCTRQQNCPIDRTSRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLHAEVQK QLQQRQQQQQEPVVKTPPAGAQGADTLTYTLGLPDGQLPLGSSPDLPEASACPPGLLKAS GSGPSYSNNLAKAGLNGASCHLEYSPERGKAEGRESFYSTGSQLTPDRCGLRFEEHRHPG LGELGQGPDSYGSPSFRSTPEAPYASLTEIEHLVQSVCKSYRETCQLRLEDLLRQRSNIF SREEVTGYQRKSMWEMWERCAHHLTEAIQYVVEFAKRLSGFMELCQNDQIVLLKAGAMEV VLVRMCRAYNADNRTVFFEGKYGGMELFRALGCSELISSIFDFSHSLSALHFSEDEIALY TALVLINAHRPGLQEKRKVEQLQYNLELAFHHHLCKTHRQSILAKLPPKGKLRSLCSQHV ERLQIFQHLHPIVVQAAFPPLYKELFSTETESPVGLSK Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
ADReCS ID | BADD_A03025 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 11 Clinical Trial Drugs | + | ||||
1 | GSK2981278 | Drug Info | Phase 2 | Plaque psoriasis | [1], [2] | |
2 | LYC-55716 | Drug Info | Phase 2 | Solid tumour/cancer | [3] | |
3 | VTP-43742 | Drug Info | Phase 2 | Psoriasis vulgaris | [1] | |
4 | ESR0114 | Drug Info | Phase 1/2 | Plaque psoriasis | [2] | |
5 | ARN-6039 | Drug Info | Phase 1 | Multiple sclerosis | [1] | |
6 | ARN-6039 | Drug Info | Phase 1 | Multiple sclerosis | [4] | |
7 | AZD0284 | Drug Info | Phase 1 | Plaque psoriasis | [2] | |
8 | BBI-6000 | Drug Info | Phase 1 | Psoriasis vulgaris | [2] | |
9 | JNJ-3534 | Drug Info | Phase 1 | Psoriasis vulgaris | [2] | |
10 | JTE-451 | Drug Info | Phase 1 | Plaque psoriasis | [2] | |
11 | TAK-828 | Drug Info | Phase 1 | Crohn disease | [1] | |
Preclinical Drug(s) | [+] 5 Preclinical Drugs | + | ||||
1 | ML209 | Drug Info | Preclinical | Autoimmune disease | [5] | |
2 | Nobiletin | Drug Info | Preclinical | Atherosclerosis | [5] | |
3 | SR1078 | Drug Info | Preclinical | Liver cancer | [5] | |
4 | SR1555 | Drug Info | Preclinical | Rheumatoid arthritis | [5] | |
5 | SR2211 | Drug Info | Preclinical | Autoimmune disease | [5] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Agonist | [+] 12 Agonist drugs | + | ||||
1 | GSK2981278 | Drug Info | [1], [2] | |||
2 | LYC-55716 | Drug Info | [3] | |||
3 | ARN-6039 | Drug Info | [6] | |||
4 | ARN-6039 | Drug Info | [7] | |||
5 | AZD0284 | Drug Info | [2] | |||
6 | TAK-828 | Drug Info | [1] | |||
7 | ML209 | Drug Info | [8] | |||
8 | Nobiletin | Drug Info | [9] | |||
9 | SR1078 | Drug Info | [10] | |||
10 | SR1555 | Drug Info | [5] | |||
11 | SR2211 | Drug Info | [5] | |||
12 | 25-hydroxycholesterol | Drug Info | [11] | |||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | VTP-43742 | Drug Info | [1] | |||
2 | ESR0114 | Drug Info | [2] | |||
3 | BBI-6000 | Drug Info | [2] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | JNJ-3534 | Drug Info | [2] | |||
Antagonist | [+] 1 Antagonist drugs | + | ||||
1 | JTE-451 | Drug Info | [2] |
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 |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | ClinicalTrials.gov (NCT03237832) A Phase 1 Study of ARN-6039 (ARN-6039). U.S. National Institutes of Health. | |||||
REF 5 | Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021 Apr;20(4):287-307. | |||||
REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 7 | Clinical pipeline report, company report or official report of Arrien Pharmaceuticals. | |||||
REF 8 | ROR nuclear receptors: structures, related diseases, and drug discovery. Acta Pharmacol Sin. 2015 Jan;36(1):71-87. | |||||
REF 9 | The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016 Apr 12;23(4):610-21. | |||||
REF 10 | Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and ROR. ACS Chem Biol. 2010 Nov 19;5(11):1029-34. | |||||
REF 11 | Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol. 2010 May;24(5):923-9. |
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