Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG5I3KU)

• DOT Name: ADP-ribosylation factor-like protein 4D (ARL4D)
• Synonyms: ADP-ribosylation factor-like protein 4L
• Gene Name: ARL4D
• Related Disease:
  Glioma
  Neoplasm
  Brain neoplasm
• UniProt ID: ARL4D_HUMAN
• Pfam ID: PF00025
• Sequence:
  MGNHLTEMAPTASSFLPHFQALHVVVIGLDSAGKTSLLYRLKFKEFVQSVPTKGFNTEKI
  RVPLGGSRGITFQVWDVGGQEKLRPLWRSYTRRTDGLVFVVDAAEAERLEEAKVELHRIS
  RASDNQGVPVLVLANKQDQPGALSAAEVEKRLAVRELAAATLTHVQGCSAVDGLGLQQGL
  ERLYEMILKRKKAARGGKKRR
• Function: Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Recruits CYTH1, CYTH2, CYTH3 and CYTH4 to the plasma membrane in GDP-bound form.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	ADP-ribosylation factor-like protein 4D (ARL4D) decreases the response to substance of Capecitabine.	[20]

15 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-like protein 4D (ARL4D).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[10]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of ADP-ribosylation factor-like protein 4D (ARL4D).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ADP-ribosylation factor-like protein 4D (ARL4D).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of ADP-ribosylation factor-like protein 4D (ARL4D).	[15]

References

• [1] Increased expression of the glioma-associated antigen ARF4L after loss of the tumor suppressor PTEN. Laboratory investigation.J Neurosurg. 2008 Feb;108(2):299-303. doi: 10.3171/JNS/2008/108/2/0299.
• [2] Recognition of ADP-ribosylation factor 4-like by HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes from patients with brain tumors.Tissue Antigens. 2002 Oct;60(4):319-27. doi: 10.1034/j.1399-0039.2002.600406.x.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [7] 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.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [11] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.