Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGV6LY)

• DTT Name: Nuclear receptor ROR-gamma (RORG)
• 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
• Gene Name: RORC
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: RORG_HUMAN
• TTD ID: T25307
• Sequence:
  MDRAPQRQHRASRELLAAKKTHTSQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRSQR
  CNAAYSCTRQQNCPIDRTSRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLHAEVQK
  QLQQRQQQQQEPVVKTPPAGAQGADTLTYTLGLPDGQLPLGSSPDLPEASACPPGLLKAS
  GSGPSYSNNLAKAGLNGASCHLEYSPERGKAEGRESFYSTGSQLTPDRCGLRFEEHRHPG
  LGELGQGPDSYGSPSFRSTPEAPYASLTEIEHLVQSVCKSYRETCQLRLEDLLRQRSNIF
  SREEVTGYQRKSMWEMWERCAHHLTEAIQYVVEFAKRLSGFMELCQNDQIVLLKAGAMEV
  VLVRMCRAYNADNRTVFFEGKYGGMELFRALGCSELISSIFDFSHSLSALHFSEDEIALY
  TALVLINAHRPGLQEKRKVEQLQYNLELAFHHHLCKTHRQSILAKLPPKGKLRSLCSQHV
  ERLQIFQHLHPIVVQAAFPPLYKELFSTETESPVGLSK
• 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.
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Circadian rhythm (hsa04710)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  RUNX3 Regulates Immune Response and Cell Migration (R-HSA-8949275)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK2981278	DM25YLM	Plaque psoriasis	EA90.0	Phase 2	[1]
LYC-55716	DMV8WU9	Non-small-cell lung cancer	2C25.Y	Phase 2	[2]
VTP-43742	DMCA8G1	Psoriasis vulgaris	EA90	Phase 2	[1]
ESR0114	DMUNM4D	Plaque psoriasis	EA90.0	Phase 1/2	[3]
ARN-6039	DM4D85V	Multiple sclerosis	8A40	Phase 1	[4]
AZD0284	DMHBEKM	Plaque psoriasis	EA90.0	Phase 1	[3]
BBI-6000	DMTG9WM	Psoriasis vulgaris	EA90	Phase 1	[3]
JNJ-3534	DM49VWQ	Psoriasis vulgaris	EA90	Phase 1	[3]
JTE-451	DM01JU8	Plaque psoriasis	EA90.0	Phase 1	[3]
TAK-828	DMW43DL	Crohn disease	DD70	Phase 1	[1]

5 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ML209	DMV2F84	Autoimmune disease	4A40-4A45	Preclinical	[5]
Nobiletin	DM7R3B6	Atherosclerosis	BD40	Preclinical	[6]
SR1078	DM7MDZE	Liver cancer	2C12	Preclinical	[7]
SR1555	DMZV9JX	Rheumatoid arthritis	FA20	Preclinical	[8]
SR2211	DMWCBG8	Autoimmune disease	4A40-4A45	Preclinical	[8]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
25-hydroxycholesterol	DMCHAQ7	Discovery agent	N.A.	Investigative	[9]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] ROR nuclear receptors: structures, related diseases, and drug discovery. Acta Pharmacol Sin. 2015 Jan;36(1):71-87.
• [6] 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.
• [7] Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and ROR. ACS Chem Biol. 2010 Nov 19;5(11):1029-34.
• [8] Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021 Apr;20(4):287-307.
• [9] Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol. 2010 May;24(5):923-9.