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] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Digoxin | Ligand Info | |||||
| Structure Description | Crystal structure of the orphan nuclear receptor ROR(gamma)t ligand-binding domain in complex with digoxin | PDB:3B0W | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [12] |
| PDB Sequence |
ASLTEIEHLV
274 QSVCKSYRET284 CQLRLEDLLR294 QRSNIFSREE304 VTGYQRKSMW314 EMWERCAHHL 324 TEAIQYVVEF334 AKRLSGFMEL344 CQNDQIVLLK354 AGAMEVVLVR364 MCRAYNADNR 374 TVFFEGKYGG384 MELFRALGCS394 ELISSIFDFS404 HSLSALHFSE414 DEIALYTALV 424 LINAHRPGLQ434 EKRKVEQLQY444 NLELAFHHHL454 CKTHRQSILA464 KLPPKGKLRS 474 LCSQH
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CYS285
4.084
GLN286
3.817
LEU287
3.554
LEU292
3.742
TRP317
3.969
CYS320
3.302
ALA321
3.883
HIS323
4.549
LEU324
4.093
ALA327
3.951
VAL361
3.871
LEU362
4.193
ARG364
3.638
MET365
3.402
ARG367
2.968
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| Ligand Name: Cholic acid | Ligand Info | |||||
| Structure Description | RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 2 AT 2.3A: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors | PDB:6Q6O | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [13] |
| PDB Sequence |
ASLTEIEHLV
274 QSVCKSYRET284 CQLRLEDLLR294 QRSNIFSREE304 VTGYQRKSMW314 EMWERCAHHL 324 TEAIQYVVEF334 AKRLSGFMEL344 CQNDQIVLLK354 AGAMEVVLVR364 MCRAYNADNR 374 TVFFEGKYGG384 MELFRALGCS394 ELISSIFDFS404 HSLSALHFSE414 DEIALYTALV 424 LINAHRPGLQ434 EKRKVEQLQY444 NLELAFHHHL454 SKTHRQSILA464 KLPPKGKLRS 474 LCSQHVERLQ484 IFQHLH
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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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| Th17 cell differentiation | hsa04659 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Circadian rhythm | hsa04710 | Affiliated Target |
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| Class: Organismal Systems => Environmental adaptation | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 2.79E-06 |
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| Closeness centrality | 2.23E-01 | Radiality | 1.39E+01 | Clustering coefficient | 4.00E-01 |
| Neighborhood connectivity | 4.26E+01 | Topological coefficient | 2.40E-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 | ||
| 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. | |||||
| REF 12 | Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production. J Biol Chem. 2011 Sep 9;286(36):31409-17. | |||||
| REF 13 | Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORGammat Inhibitors. J Med Chem. 2019 Dec 12;62(23):10816-10832. | |||||
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