Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8LHMDH)

• DOT Name: Retinoic acid receptor gamma (RARG)
• Synonyms: RAR-gamma; Nuclear receptor subfamily 1 group B member 3
• Gene Name: RARG
• UniProt ID: RARG_HUMAN
• PDB ID: 1EXA; 1EXX; 1FCX; 1FCY; 1FCZ; 1FD0; 2LBD; 3LBD; 4LBD; 5M24; 6FX0
• Pfam ID: PF00104 ; PF00105
• 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.
• Tissue Specificity: Expressed in aortic endothelial cells (at protein level).
• Reactome Pathway:
  Signaling by Retinoic Acid (R-HSA-5362517)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Retinoic acid receptor gamma (RARG) increases the response to substance of Daunorubicin.	[17]
Afimoxifene	DMFORDT	Phase 2	Retinoic acid receptor gamma (RARG) affects the response to substance of Afimoxifene.	[18]
PMID27336223-Compound-11	DMBN6KU	Patented	Retinoic acid receptor gamma (RARG) affects the response to substance of PMID27336223-Compound-11.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinoic acid receptor gamma (RARG).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinoic acid receptor gamma (RARG).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Retinoic acid receptor gamma (RARG).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinoic acid receptor gamma (RARG).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Retinoic acid receptor gamma (RARG).	[5]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Retinoic acid receptor gamma (RARG).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Retinoic acid receptor gamma (RARG).	[7]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Retinoic acid receptor gamma (RARG).	[8]
Ezetimibe	DM7A8TW	Approved	Ezetimibe decreases the expression of Retinoic acid receptor gamma (RARG).	[9]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Retinoic acid receptor gamma (RARG).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Retinoic acid receptor gamma (RARG).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Retinoic acid receptor gamma (RARG).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Retinoic acid receptor gamma (RARG).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Retinoic acid receptor gamma (RARG).	[13]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the activity of Retinoic acid receptor gamma (RARG).	[14]
TTNPB	DMSABD0	Investigative	TTNPB increases the activity of Retinoic acid receptor gamma (RARG).	[15]
chlordane	DMMHU8G	Investigative	chlordane increases the expression of Retinoic acid receptor gamma (RARG).	[16]

References

• [1] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [6] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [7] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [8] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [9] Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J Nutr. 2005 Oct;135(10):2305-12. doi: 10.1093/jn/135.10.2305.
• [10] Breast cancer progression in MCF10A series of cell lines is associated with alterations in retinoic acid and retinoid X receptors and with differential response to retinoids. Int J Oncol. 2004 Oct;25(4):961-71.
• [11] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids. Mol Pharmacol. 2015;87(3):430-41.
• [15] The retinoic acid receptor (RAR) in molluscs: Function, evolution and endocrine disruption insights. Aquat Toxicol. 2019 Mar;208:80-89. doi: 10.1016/j.aquatox.2019.01.002. Epub 2019 Jan 7.
• [16] Activation of retinoic acid receptor-dependent transcription by organochlorine pesticides. Toxicol Appl Pharmacol. 2005 Jan 1;202(1):38-49.
• [17] A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015 Sep;47(9):1079-84. doi: 10.1038/ng.3374. Epub 2015 Aug 3.
• [18] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.
• [19] Pharmacology of adapalene. Br J Dermatol. 1998 Oct;139 Suppl 52:3-7. doi: 10.1046/j.1365-2133.1998.1390s2003.x.