Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT254B09)

• DOT Name: Retinoic acid receptor RXR-gamma (RXRG)
• Synonyms: Nuclear receptor subfamily 2 group B member 3; Retinoid X receptor gamma
• Gene Name: RXRG
• UniProt ID: RXRG_HUMAN
• PDB ID: 2GL8; 7A79
• Pfam ID: PF00104 ; PF11825 ; PF00105
• Sequence:
  MYGNYSHFMKFPAGYGGSPGHTGSTSMSPSAALSTGKPMDSHPSYTDTPVSAPRTLSAVG
  TPLNALGSPYRVITSAMGPPSGALAAPPGINLVAPPSSQLNVVNSVSSSEDIKPLPGLPG
  IGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLIYTCRDNKD
  CLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECATSGHEDMPVERIL
  EAELAVEPKTESYGDMNMENSTNDPVTNICHAADKQLFTLVEWAKRIPHFSDLTLEDQVI
  LLRAGWNELLIASFSHRSVSVQDGILLATGLHVHRSSAHSAGVGSIFDRVLTELVSKMKD
  MQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTKQKYPEQPGRFAKLL
  LRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLETPLQIT
• 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. The high affinity ligand for RXRs is 9-cis retinoic acid.
• Tissue Specificity: Expressed in aortic endothelial cells (at protein level).
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Th17 cell differentiation (hsa04659)
  Thyroid hormone sig.ling pathway (hsa04919)
  Adipocytokine sig.ling pathway (hsa04920)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  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:
  Signaling by Retinoic Acid (R-HSA-5362517)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Retinoic acid receptor RXR-gamma (RXRG).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[4]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[7]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Retinoic acid receptor RXR-gamma (RXRG).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Retinoic acid receptor RXR-gamma (RXRG).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinoic acid receptor RXR-gamma (RXRG).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Retinoic acid receptor RXR-gamma (RXRG).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[6]
Bexarotene	DMOBIKY	Approved	Bexarotene affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[6]
Bezafibrate	DMZDCS0	Approved	Bezafibrate affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[6]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[6]
M-Phenoxybenzoic Acid For Cis-Isomer	DMJRK47	Investigative	M-Phenoxybenzoic Acid For Cis-Isomer affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[11]
Phthalic Acid	DMF9T64	Investigative	Phthalic Acid affects the binding of Retinoic acid receptor RXR-gamma (RXRG).	[6]

References

• [1] Mechanisms of induction of human tissue inhibitor of metalloproteinases-1 (TIMP-1) gene expression by all-trans retinoic acid in combination with basic fibroblast growth factor. Eur J Biochem. 2000 Jul;267(13):4150-6. doi: 10.1046/j.1432-1327.2000.01459.x.
• [2] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [6] Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor , , subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11.
• [7] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [8] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Structure-based Identification of Endocrine Disrupting Pesticides Targeting Breast Cancer Proteins. Toxicology. 2020 Jun;439:152459. doi: 10.1016/j.tox.2020.152459. Epub 2020 Apr 9.