Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT192V9V)

• DOT Name: Retinoic acid receptor alpha (RARA)
• Synonyms: RAR-alpha; Nuclear receptor subfamily 1 group B member 1
• Gene Name: RARA
• Related Disease:
  Multiple congenital anomalies/dysmorphic syndrome
  Promyelocytic leukaemia
• UniProt ID: RARA_HUMAN
• PDB ID: 1DKF; 1DSZ; 3A9E; 3KMR; 3KMZ; 4DQM; 5K13; 6XWG; 7AOS; 7APO; 7QAA; 7WQQ
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTTLQHQLPVSGYSTPSPAT
  IETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNM
  VYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKEVPKPECSESYTL
  TPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDLWDKFSELSTKCIIKTV
  EFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGLTLNRTQMHNA
  GFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGDRQDLEQPDRVDMLQEPLLEALK
  VYVRKRRPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEMLENSEGL
  DTLSGQPGGGGRDGGGLAPPPGSCSPSLSPSSNRSSPATHSP
• 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 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 deacetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression. Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2. 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. Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells. In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response.
• Tissue Specificity: Expressed in monocytes.
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Estrogen sig.ling pathway (hsa04915)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  SUMOylation of intracellular receptors (R-HSA-4090294)
  Signaling by Retinoic Acid (R-HSA-5362517)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Limited	Autosomal dominant	[1]
Promyelocytic leukaemia	DISYGG13	No Known	Autosomal dominant	[1]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Retinoic acid receptor alpha (RARA) decreases the response to substance of Tretinoin.	[29]
Arsenic trioxide	DM61TA4	Approved	Retinoic acid receptor alpha (RARA) decreases the response to substance of Arsenic trioxide.	[30]
Etretinate	DM2CZFA	Approved	Retinoic acid receptor alpha (RARA) increases the Hypertriglyceridaemia ADR of Etretinate.	[31]
Tamibarotene	DM3G74J	Phase 3	Retinoic acid receptor alpha (RARA) decreases the response to substance of Tamibarotene.	[32]
Ro 41-5253	DMSJLWP	Investigative	Retinoic acid receptor alpha (RARA) increases the response to substance of Ro 41-5253.	[33]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Retinoic acid receptor alpha (RARA).	[2]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of Retinoic acid receptor alpha (RARA).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Retinoic acid receptor alpha (RARA).	[22]
MG-132	DMKA2YS	Preclinical	MG-132 increases the ubiquitination of Retinoic acid receptor alpha (RARA).	[25]

33 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinoic acid receptor alpha (RARA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinoic acid receptor alpha (RARA).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Retinoic acid receptor alpha (RARA).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Retinoic acid receptor alpha (RARA).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Retinoic acid receptor alpha (RARA).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Retinoic acid receptor alpha (RARA).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Retinoic acid receptor alpha (RARA).	[10]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Retinoic acid receptor alpha (RARA).	[11]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Retinoic acid receptor alpha (RARA).	[3]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone affects the mutagenesis of Retinoic acid receptor alpha (RARA).	[12]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Retinoic acid receptor alpha (RARA).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Lindane	DMB8CNL	Approved	Lindane increases the activity of Retinoic acid receptor alpha (RARA).	[14]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of Retinoic acid receptor alpha (RARA).	[15]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Retinoic acid receptor alpha (RARA).	[3]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Retinoic acid receptor alpha (RARA).	[15]
Epirubicin	DMPDW6T	Approved	Epirubicin affects the mutagenesis of Retinoic acid receptor alpha (RARA).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Retinoic acid receptor alpha (RARA).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Retinoic acid receptor alpha (RARA).	[17]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Retinoic acid receptor alpha (RARA).	[18]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl affects the expression of Retinoic acid receptor alpha (RARA).	[20]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Retinoic acid receptor alpha (RARA).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Retinoic acid receptor alpha (RARA).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Retinoic acid receptor alpha (RARA).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Retinoic acid receptor alpha (RARA).	[26]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Retinoic acid receptor alpha (RARA).	[27]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Retinoic acid receptor alpha (RARA).	[15]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Retinoic acid receptor alpha (RARA).	[16]
Caffeic acid phenethyl ester	DMRJKIV	Investigative	Caffeic acid phenethyl ester increases the expression of Retinoic acid receptor alpha (RARA).	[28]

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