Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3OGOMX)

• DOT Name: ADP-ribosylation factor-like protein 3 (ARL3)
• Gene Name: ARL3
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Hereditary hemochromatosis
  Advanced cancer
  Autosomal recessive polycystic kidney disease
  Glioma
  Joubert syndrome 1
  Joubert syndrome 17
  Joubert syndrome 35
  Retinitis pigmentosa 2
  Retinitis pigmentosa 83
  Schizophrenia
  Joubert syndrome
  Retinitis pigmentosa
• UniProt ID: ARL3_HUMAN
• Pfam ID: PF00025
• Sequence:
  MGLLSILRKLKSAPDQEVRILLLGLDNAGKTTLLKQLASEDISHITPTQGFNIKSVQSQG
  FKLNVWDIGGQRKIRPYWKNYFENTDILIYVIDSADRKRFEETGQELAELLEEEKLSCVP
  VLIFANKQDLLTAAPASEIAEGLNLHTIRDRVWQIQSCSALTGEGVQDGMNWVCKNVNAK
  KK
• 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). Required for normal cytokinesis and cilia signaling. Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms. Required for targeting proteins to the cilium, including myristoylated NPHP3 and prenylated INPP5E. Targets NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium. Required for PKD1:PKD2 complex targeting from the trans-Golgi network to the cilium.
• Tissue Specificity: Expressed in the retina. Strongly expressed in connecting cilium, the myoid region of the inner segments (IS) and in cone photoreceptors (at protein level).
• Reactome Pathway: Trafficking of myristoylated proteins to the cilium (R-HSA-5624138)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Genetic Variation	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[1]
Hereditary hemochromatosis	DISVG5MT	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[5]
Joubert syndrome 17	DIS9LHZ1	Strong	Autosomal recessive	[5]
Joubert syndrome 35	DISGTP4K	Strong	Autosomal recessive	[5]
Retinitis pigmentosa 2	DISLBNCM	Strong	Biomarker	[2]
Retinitis pigmentosa 83	DISEQJW1	Strong	Autosomal dominant	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[7]

2 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 3 (ARL3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ADP-ribosylation factor-like protein 3 (ARL3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ADP-ribosylation factor-like protein 3 (ARL3).	[19]

References

• [1] Homozygous Variant in ARL3 Causes Autosomal Recessive Cone Rod Dystrophy.Invest Ophthalmol Vis Sci. 2019 Nov 1;60(14):4811-4819. doi: 10.1167/iovs.19-27263.
• [2] Arl3 and RP2 regulate the trafficking of ciliary tip kinesins.Hum Mol Genet. 2017 Jul 1;26(13):2480-2492. doi: 10.1093/hmg/ddx143.
• [3] ARL3 is downregulated and acts as a prognostic biomarker in glioma.J Transl Med. 2019 Jun 24;17(1):210. doi: 10.1186/s12967-019-1914-3.
• [4] ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development. Am J Pathol. 2006 Apr;168(4):1288-98. doi: 10.2353/ajpath.2006.050941.
• [5] ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. Am J Hum Genet. 2018 Oct 4;103(4):612-620. doi: 10.1016/j.ajhg.2018.08.015. Epub 2018 Sep 27.
• [6] Common variants on 2p16.1, 6p22.1 and 10q24.32 are associated with schizophrenia in Han Chinese population.Mol Psychiatry. 2017 Jul;22(7):954-960. doi: 10.1038/mp.2016.212. Epub 2016 Dec 6.
• [7] De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. PLoS One. 2016 Mar 10;11(3):e0150944. doi: 10.1371/journal.pone.0150944. eCollection 2016.
• [8] 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.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [13] 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.
• [14] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [15] 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.
• [16] 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.
• [17] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.