Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTINJ0FX)

• DOT Name: Arrestin domain-containing protein 4 (ARRDC4)
• Gene Name: ARRDC4
• Related Disease:
  Congenital diaphragmatic hernia
  Lactic acidosis
  Enterovirus infection
  Type-1/2 diabetes
• UniProt ID: ARRD4_HUMAN
• Pfam ID: PF02752 ; PF00339
• Sequence:
  MGGEAGCAAAVGAEGRVKSLGLVFEDERKGCYSSGETVAGHVLLEASEPVALRALRLEAQ
  GRATAAWGPSTCPRASASTAALAVFSEVEYLNVRLSLREPPAGEGIILLQPGKHEFPFRF
  QLPSEPLVTSFTGKYGSIQYCVRAVLERPKVPDQSVKRELQVVSHVDVNTPALLTPVLKT
  QEKMVGCWFFTSGPVSLSAKIERKGYCNGEAIPIYAEIENCSSRLIVPKAAIFQTQTYLA
  SGKTKTIRHMVANVRGNHIASGSTDTWNGKTLKIPPVTPSILDCCIIRVDYSLAVYIHIP
  GAKKLMLELPLVIGTIPYNGFGSRNSSIASQFSMDMSWLTLTLPEQPEAPPNYADVVSEE
  EFSRHIPPYPQPPNCEGEVCCPVFACIQEFRFQPPPLYSEVDPHPSDVEESQPVSFIL
• Function: Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates. Plays a role in endocytosis of activated G protein-coupled receptors (GPCRs) (Probable). Through an ubiquitination-dependent mechanism also plays a role in the incorporation of SLC11A2 into extracellular vesicles. May play a role in glucose uptake. Participates in innate immune response by promoting IFIH1/MDA5 activation through interaction with TRIM65.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Genetic Variation	[1]
Lactic acidosis	DISZI1ZK	Strong	Altered Expression	[2]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Arrestin domain-containing protein 4 (ARRDC4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[14]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[15]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[18]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[22]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[15]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[25]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Arrestin domain-containing protein 4 (ARRDC4).	[26]

References

• [1] Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1-15q26.2.Eur J Hum Genet. 2006 Sep;14(9):999-1008. doi: 10.1038/sj.ejhg.5201652. Epub 2006 May 31.
• [2] Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA.PLoS Genet. 2010 Sep 2;6(9):e1001093. doi: 10.1371/journal.pgen.1001093.
• [3] ARRDC4 regulates enterovirus 71-induced innate immune response by promoting K63 polyubiquitination of MDA5 through TRIM65.Cell Death Dis. 2017 Jun 8;8(6):e2866. doi: 10.1038/cddis.2017.257.
• [4] MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic -Cells.Diabetes. 2018 Mar;67(3):461-472. doi: 10.2337/db17-0595. Epub 2017 Dec 27.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] 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.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [25] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.
• [26] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.