Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2OU9R2)

• DOT Name: ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6)
• Synonyms: ARL-6-interacting protein 6; Aip-6; Phosphonoformate immuno-associated protein 1
• Gene Name: ARL6IP6
• Related Disease:
  Vascular malformation
  Stroke
  Colorectal carcinoma
• UniProt ID: AR6P6_HUMAN
• Pfam ID: PF15062
• Sequence:
  MSFAESGWRSALRRRGPGTPGPVARPSYSSFTQGDSWGEGEVDEEEGCDQVARDLRAEFS
  AGAWSEPRKRSVLPPDGNGSPVLPDKRNGIFPAAAGSRAQPRRWPVQVLSILCSLLFAIL
  LAFLLAIAYLIVKELHAENLKNEDDVDTGLLGFWTLLIISLTAGFSCCSFSWTVTYFDSF
  EPGMFPPTPLSPARFKKLTGHSFHMGYSMAILNGIVAALTVAWCLM

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vascular malformation	DIS2DB7A	Strong	Genetic Variation	[1]
Stroke	DISX6UHX	moderate	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[3]

3 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 ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[12]

10 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 ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 6 (ARL6IP6).	[14]

References

• [1] ARL6IP6, a susceptibility locus for ischemic stroke, is mutated in a patient with syndromic Cutis Marmorata Telangiectatica Congenita. Hum Genet. 2015 Aug;134(8):815-22. doi: 10.1007/s00439-015-1561-6. Epub 2015 May 10.
• [2] Genome-wide association analysis of ischemic stroke in young adults.G3 (Bethesda). 2011 Nov;1(6):505-14. doi: 10.1534/g3.111.001164. Epub 2011 Nov 1.
• [3] TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles.Mol Oncol. 2008 Oct;2(3):233-40. doi: 10.1016/j.molonc.2008.06.003. Epub 2008 Jun 18.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.