Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3GMDHA)

• DOT Name: ADP-ribosylation factor 4 (ARF4)
• Gene Name: ARF4
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
• UniProt ID: ARF4_HUMAN
• PDB ID: 1Z6X
• Pfam ID: PF00025
• Sequence:
  MGLTISSLFSRLFGKKQMRILMVGLDAAGKTTILYKLKLGEIVTTIPTIGFNVETVEYKN
  ICFTVWDVGGQDRIRPLWKHYFQNTQGLIFVVDSNDRERIQEVADELQKMLLVDELRDAV
  LLLFANKQDLPNAMAISEMTDKLGLQSLRNRTWYVQATCATQGTGLYEGLDWLSNELSKR
• Function: GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus. Part of the ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which direct preciliary vesicle trafficking to mother centriole and ciliogenesis initiation.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  VxPx cargo-targeting to cilium (R-HSA-5620916)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	moderate	Biomarker	[2]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of ADP-ribosylation factor 4 (ARF4).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ADP-ribosylation factor 4 (ARF4).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribosylation factor 4 (ARF4).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of ADP-ribosylation factor 4 (ARF4).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ADP-ribosylation factor 4 (ARF4).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ADP-ribosylation factor 4 (ARF4).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ADP-ribosylation factor 4 (ARF4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor 4 (ARF4).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of ADP-ribosylation factor 4 (ARF4).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of ADP-ribosylation factor 4 (ARF4).	[13]

References

• [1] Identification of ADP-ribosylation factor 4 as a suppressor of N-(4-hydroxyphenyl)retinamide-induced cell death.Cancer Lett. 2009 Apr 8;276(1):53-60. doi: 10.1016/j.canlet.2008.10.031. Epub 2008 Nov 28.
• [2] Regulation of ADP-ribosylation factor 4 expression by small leucine zipper protein and involvement in breast cancer cell migration.Cancer Lett. 2012 Jan 28;314(2):185-97. doi: 10.1016/j.canlet.2011.09.028. Epub 2011 Sep 29.
• [3] Investigation of the role of GBF1 in the replication of positive-sense single-stranded RNA viruses.J Gen Virol. 2018 Aug;99(8):1086-1096. doi: 10.1099/jgv.0.001099. Epub 2018 Jun 20.
• [4] 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.
• [5] 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.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [11] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [12] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [13] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.