Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTW38KT)

• DTT Name: Retinoic acid receptor alpha (RARA)
• Synonyms: RAR-alpha; RAR alpha; Nuclear receptor subfamily 1 group B member 1; NR1B1
• Gene Name: RARA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: RARA_HUMAN
• TTD ID: T94085
• Sequence:
  MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTTLQHQLPVSGYSTPSPAT
  IETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNM
  VYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKEVPKPECSESYTL
  TPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDLWDKFSELSTKCIIKTV
  EFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGLTLNRTQMHNA
  GFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGDRQDLEQPDRVDMLQEPLLEALK
  VYVRKRRPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEMLENSEGL
  DTLSGQPGGGGRDGGGLAPPPGSCSPSLSPSSNRSSPATHSP
• Function: 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 RXR/RAR 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, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Receptor for retinoic acid.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tamibarotene	DM3G74J	T-cell leukaemia	2A90	Phase 3	[2]
IRX-5183	DMCED9U	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
SY-1425	DMH8UF0	Acute myeloid leukaemia	2A60	Phase 1	[4]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID27336223-Compound-4	DMJFSOM	N. A.	N. A.	Patented	[5]
PMID27336223-Compound-5	DM6E50A	N. A.	N. A.	Patented	[5]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LG100268	DM41RK2	Acquired immune deficiency syndrome	1C62.3	Discontinued in Phase 1	[6]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AGN193109	DMC0YOE	Discovery agent	N.A.	Investigative	[7]
AGN193836	DMEB93D	Discovery agent	N.A.	Investigative	[8]
BMS614	DMZWNO9	Discovery agent	N.A.	Investigative	[9]
BMS753	DMSX1NF	Discovery agent	N.A.	Investigative	[10]
CD666	DMC8X9Y	Discovery agent	N.A.	Investigative	[11]
Ro 40-6055	DMU2EKN	Discovery agent	N.A.	Investigative	[12]
Ro 41-5253	DMSJLWP	Discovery agent	N.A.	Investigative	[13]
Ro-40-0655	DM8PYAN	Colorectal cancer	2B91.Z	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	4.46E-01	-0.04	-0.13
Rectal cancer	2C82	Rectal colon tissue	5.76E-02	-0.18	-1.14
Sarcoma	2C82	Muscle tissue	5.39E-05	0.16	0.41

References

• [1] 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.
• [2] Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol Pharm Bull. 2012;35(8):1206-12.
• [3] Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat. J Mol Med (Berl). 2004 Feb;82(2):116-25.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.Expert Opin Ther Pat. 2016 Aug;26(8):957-71.
• [6] Placental steroidogenesis in rats is independent of signaling pathways induced by retinoic acids. Gen Comp Endocrinol. 2009 Sep 15;163(3):285-91.
• [7] Therapeutic applications for ligands of retinoid receptors. Curr Pharm Des. 2000 Jan;6(1):25-58.
• [8] Synthesis and biological activity of retinoic acid receptor-alpha specific amides. Bioorg Med Chem Lett. 2002 Nov 4;12(21):3145-8.
• [9] Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature. 2002 Jan 10;415(6868):187-92.
• [10] Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. Chem Biol. 1999 Aug;6(8):519-29.
• [11] Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun. 1992 Jul 31;186(2):977-83.
• [12] Selective high affinity retinoic acid receptor alpha or beta-gamma ligands. Mol Pharmacol. 1991 Oct;40(4):556-62.
• [13] A retinoic acid receptor alpha antagonist selectively counteracts retinoic acid effects. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7129-33.
• [14] Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8.