Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP1TBDM)

• DOT Name: Retinoic acid receptor RXR-alpha (RXRA)
• Synonyms: Nuclear receptor subfamily 2 group B member 1; Retinoid X receptor alpha
• Gene Name: RXRA
• UniProt ID: RXRA_HUMAN
• PDB ID: 1BY4 ; 1DSZ ; 1FBY ; 1FM6 ; 1FM9 ; 1G1U ; 1G5Y ; 1K74 ; 1MV9 ; 1MVC ; 1MZN ; 1R0N ; 1RDT ; 1RXR ; 1XLS ; 1XV9 ; 1XVP ; 1YNW ; 2ACL ; 2NLL ; 2P1T ; 2P1U ; 2P1V ; 2ZXZ ; 2ZY0 ; 3DZU ; 3DZY ; 3E00 ; 3E94 ; 3FAL ; 3FC6 ; 3FUG ; 3H0A ; 3KWY ; 3NSP ; 3NSQ ; 3OAP ; 3OZJ ; 3PCU ; 3R29 ; 3R2A ; 3R5M ; 3UVV ; 4CN2 ; 4CN3 ; 4CN5 ; 4CN7 ; 4J5W ; 4J5X ; 4K4J ; 4K6I ; 4M8E ; 4M8H ; 4N5G ; 4N8R ; 4NQA ; 4OC7 ; 4POH ; 4POJ ; 4PP3 ; 4PP5 ; 4RFW ; 4RMC ; 4RMD ; 4RME ; 4ZO1 ; 4ZSH ; 5EC9 ; 5JI0 ; 5LYQ ; 5MJ5 ; 5MK4 ; 5MKJ ; 5MKU ; 5MMW ; 5TBP ; 5UAN ; 5Z12 ; 5ZQU ; 6A5Y ; 6A5Z ; 6A60 ; 6FBQ ; 6FBR ; 6HN6 ; 6JNO ; 6JNR ; 6L6K ; 6LB4 ; 6LB5 ; 6LB6 ; 6SJM ; 6STI ; 6XWG ; 6XWH ; 7A77 ; 7B88 ; 7B9O ; 7BK4 ; 7CFO ; 7NKE ; 7UW2 ; 7UW4 ; 8HBM
• Pfam ID: PF00104 ; PF11825 ; PF00105
• Sequence:
  MDTKHFLPLDFSTQVNSSLTSPTGRGSMAAPSLHPSLGPGIGSPGQLHSPISTLSSPING
  MGPPFSVISSPMGPHSMSVPTTPTLGFSTGSPQLSSPMNPVSSSEDIKPPLGLNGVLKVP
  AHPSGNMASFTKHICAICGDRSSGKHYGVYSCEGCKGFFKRTVRKDLTYTCRDNKDCLID
  KRQRNRCQYCRYQKCLAMGMKREAVQEERQRGKDRNENEVESTSSANEDMPVERILEAEL
  AVEPKTETYVEANMGLNPSSPNDPVTNICQAADKQLFTLVEWAKRIPHFSELPLDDQVIL
  LRAGWNELLIASFSHRSIAVKDGILLATGLHVHRNSAHSAGVGAIFDRVLTELVSKMRDM
  QMDKTELGCLRAIVLFNPDSKGLSNPAEVEALREKVYASLEAYCKHKYPEQPGRFAKLLL
  RLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQMT
• Function: Receptor for retinoic acid that acts as a transcription factor. Forms homo- or heterodimers with retinoic acid receptors (RARs) and binds to target response elements in response to their ligands, all-trans or 9-cis retinoic acid, to 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 to regulate transcription. The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid. 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 coactivators are recruited leading to transcriptional activation. Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA. The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells. Acts as an enhancer of RARA binding to RARE DNA element. May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1. Promotes myelin debris phagocytosis and remyelination by macrophages. Plays a role in the attenuation of the innate immune system in response to viral infections, possibly by negatively regulating the transcription of antiviral genes such as type I IFN genes. Involved in the regulation of calcium signaling by repressing ITPR2 gene expression, thereby controlling cellular senescence.
• Tissue Specificity: Expressed in lung fibroblasts (at protein level) . Expressed in monocytes . Highly expressed in liver, also found in kidney and brain .
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Efferocytosis (hsa04148)
  PI3K-Akt sig.ling pathway (hsa04151)
  Th17 cell differentiation (hsa04659)
  Thyroid hormone sig.ling pathway (hsa04919)
  Adipocytokine sig.ling pathway (hsa04920)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Non-alcoholic fatty liver disease (hsa04932)
  Bile secretion (hsa04976)
  Hepatitis C (hsa05160)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Thyroid cancer (hsa05216)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Gastric cancer (hsa05226)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  Recycling of bile acids and salts (R-HSA-159418)
  Synthesis of bile acids and bile salts (R-HSA-192105)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  PPARA activates gene expression (R-HSA-1989781)
  Carnitine metabolism (R-HSA-200425)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)
  Endogenous sterols (R-HSA-211976)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  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)
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake (R-HSA-9031525)
  NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose (R-HSA-9031528)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis (R-HSA-9623433)
  NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis (R-HSA-9632974)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Retinoic acid receptor RXR-alpha (RXRA) increases the Renal failure acute ADR of Cisplatin.	[41]
Troglitazone	DM3VFPD	Approved	Retinoic acid receptor RXR-alpha (RXRA) decreases the response to substance of Troglitazone.	[42]
Chlorothiazide	DMLHESP	Approved	Retinoic acid receptor RXR-alpha (RXRA) increases the Neutropenia ADR of Chlorothiazide.	[43]
Etretinate	DM2CZFA	Approved	Retinoic acid receptor RXR-alpha (RXRA) increases the Hypertriglyceridaemia ADR of Etretinate.	[41]

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 RXR-alpha (RXRA).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinoic acid receptor RXR-alpha (RXRA).	[26]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Retinoic acid receptor RXR-alpha (RXRA).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Retinoic acid receptor RXR-alpha (RXRA).	[30]

37 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 RXR-alpha (RXRA).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Retinoic acid receptor RXR-alpha (RXRA).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Retinoic acid receptor RXR-alpha (RXRA).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[2]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[16]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[2]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[17]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[2]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[23]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[24]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[27]
IRX4204	DM9SCME	Phase 1	IRX4204 increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[29]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[14]
MK-886	DMT0O7H	Discontinued in Phase 2	MK-886 increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[31]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[32]
Aphidicolin	DM71C6D	Discontinued in Phase 1	Aphidicolin increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[33]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[34]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[38]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) increases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[39]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the expression of Retinoic acid receptor RXR-alpha (RXRA).	[23]
TTNPB	DMSABD0	Investigative	TTNPB increases the activity of Retinoic acid receptor RXR-alpha (RXRA).	[14]

18 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bexarotene	DMOBIKY	Approved	Bexarotene affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[18]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol affects the localization of Retinoic acid receptor RXR-alpha (RXRA).	[19]
Bezafibrate	DMZDCS0	Approved	Bezafibrate affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[18]
Acitretin	DM8BKU9	Approved	Acitretin affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[21]
Alfacalcidol	DM1237M	Phase 4	Alfacalcidol affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[22]
ED-71	DMRLXAI	Phase 3	ED-71 affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[22]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the degradation of Retinoic acid receptor RXR-alpha (RXRA).	[25]
tiratricol	DMZO6CV	Clinical trial	tiratricol affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[21]
SR-11237	DMQG3CK	Terminated	SR-11237 affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[37]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[36]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[18]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[36]
L-thyroxine	DM83HWL	Investigative	L-thyroxine affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[21]
Dimethylformamide	DML6O4N	Investigative	Dimethylformamide decreases the degradation of Retinoic acid receptor RXR-alpha (RXRA).	[40]
Alpha-linolenic acid	DMY64HE	Investigative	Alpha-linolenic acid affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[36]
Phthalic Acid	DMF9T64	Investigative	Phthalic Acid affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[18]
Equilin	DM2Q19U	Investigative	Equilin affects the binding of Retinoic acid receptor RXR-alpha (RXRA).	[21]

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