Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1Q3IE)

• DTT Name: Retinoic acid receptor gamma (RARG)
• Synonyms: RAR-gamma; Nuclear receptor subfamily 1 group B member 3; NR1B3
• Gene Name: RARG
• DTT Type: Successful target; [1]
• Related Disease:
  Acne vulgaris [ICD-11: ED80]
  Acute myeloid leukaemia [ICD-11: 2A60]
  Kaposi sarcoma [ICD-11: 2B57]
  Psoriasis [ICD-11: EA90]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: RARG_HUMAN
• TTD ID: T82146
• Sequence:
  MATNKERLFAAGALGPGSGYPGAGFPFAFPGALRGSPPFEMLSPSFRGLGQPDLPKEMAS
  LSVETQSTSSEEMVPSSPSPPPPPRVYKPCFVCNDKSSGYHYGVSSCEGCKGFFRRSIQK
  NMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKEAVRNDRNKKKKEVKEEGSPDSY
  ELSPQLEELITKVSKAHQETFPSLCQLGKYTTNSSADHRVQLDLGLWDKFSELATKCIIK
  IVEFAKRLPGFTGLSIADQITLLKAACLDILMLRICTRYTPEQDTMTFSDGLTLNRTQMH
  NAGFGPLTDLVFAFAGQLLPLEMDDTETGLLSAICLICGDRMDLEEPEKVDKLQEPLLEA
  LRLYARRRRPSQPYMFPRMLMKITDLRGISTKGAERAITLKMEIPGPMPPLIREMLENPE
  MFEDDSSQPGPHPNASSEDEVPGGQGKGGLKSPA
• Function: Receptor for retinoic acid. 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. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alitretinoin	DMME8LH	Kaposi sarcoma	2B57	Approved	[2], [3], [4]
Tazarotene	DM8SMD1	Psoriasis vulgaris	EA90	Approved	[1]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[3]
Trifarotene	DMOL793	Acne vulgaris	ED80	Approved	[5]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Palovarotene	DMAD2OZ	Fibrodysplasia ossificans progressiva	FB31.1	Phase 3	[6]

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID27336223-Compound-11	DMBN6KU	N. A.	N. A.	Patented	[7]
PMID27336223-Compound-12	DMT4P7K	N. A.	N. A.	Patented	[7]
PMID27336223-Compound-13	DMSZLYD	N. A.	N. A.	Patented	[7]
PMID27336223-Compound-14	DMC41MA	N. A.	N. A.	Patented	[7]
PMID27336223-Compound-15	DMIYCFE	N. A.	N. A.	Patented	[7]
PMID27336223-Compound-9	DM6V13W	N. A.	N. A.	Patented	[7]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AGN193109	DMC0YOE	Discovery agent	N.A.	Investigative	[8]
AHPN	DM8G6O4	Discovery agent	N.A.	Investigative	[9]
BMS184394	DMGE82R	Discovery agent	N.A.	Investigative	[10]
BMS270394	DM82SJP	Discovery agent	N.A.	Investigative	[11]
CD2665	DM05M9X	Discovery agent	N.A.	Investigative	[12]
CD564	DMZ2LPO	Discovery agent	N.A.	Investigative	[10]
CD666	DMC8X9Y	Discovery agent	N.A.	Investigative	[13]
Dodecyl-Alpha-D-Maltoside	DMMDG92	Discovery agent	N.A.	Investigative	[14]
MM 11253	DMT1NP8	Discovery agent	N.A.	Investigative	[15]
SR11254	DMBA297	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Sarcoma	2C82	Muscle tissue	5.43E-04	-0.14	-0.37
Psoriasis	EA90	Skin	2.11E-08	-0.77	-0.93
Chronic obstructive pulmonary disease	CA23	Lung tissue	1.81E-01	0.07	0.2
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.45E-03	-0.13	-0.39

References

• [1] Recent developments in receptor-selective retinoids. Curr Pharm Des. 2000 Jun;6(9):919-31.
• [2] 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.
• [3] Targacept active conformation search: a new method for predicting the conformation of a ligand bound to its protein target. J Med Chem. 2004 Dec 30;47(27):6831-9.
• [4] Alitretinoin: a comprehensive review. Expert Opin Investig Drugs. 2008 Mar;17(3):437-43.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [6] Randomised controlled trial for emphysema with a selective agonist of the gamma-type retinoic acid receptor. Eur Respir J. 2012 Aug;40(2):306-12.
• [7] Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.Expert Opin Ther Pat. 2016 Aug;26(8):957-71.
• [8] Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des. 2000 Jan;6(1):25-58.
• [9] Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J Med Chem. 1995 Dec 22;38(26):4993-5006.
• [10] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [11] Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6322-7.
• [12] Induction of apoptosis by retinoids and retinoic acid receptor gamma-selective compounds in mouse thymocytes through a novel apoptosis pathway. Mol Pharmacol. 1997 Jun;51(6):972-82.
• [13] Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun. 1992 Jul 31;186(2):977-83.
• [14] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [15] Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids. Oncogene. 2000 Mar 9;19(11):1457-65.