Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTICNK0O)

• DOT Name: ADP-ribosylation factor-like protein 2 (ARL2)
• Gene Name: ARL2
• Related Disease: Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1
• UniProt ID: ARL2_HUMAN
• PDB ID: 3DOE; 3DOF
• Pfam ID: PF00025
• Sequence:
  MGLLTILKKMKQKERELRLLMLGLDNAGKTTILKKFNGEDIDTISPTLGFNIKTLEHRGF
  KLNIWDVGGQKSLRSYWRNYFESTDGLIWVVDSADRQRMQDCQRELQSLLVEERLAGATL
  LIFANKQDLPGALSSNAIREVLELDSIRSHHWCIQGCSAVTGENLLPGIDWLLDDISSRI
  FTAD
• 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. Regulates formation of new microtubules and centrosome integrity. Prevents the TBCD-induced microtubule destruction. Participates in association with TBCD, in the disassembly of the apical junction complexes. Antagonizes the effect of TBCD on epithelial cell detachment and tight and adherens junctions disassembly. Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. Component of a regulated secretory pathway involved in Ca(2+)-dependent release of acetylcholine. Required for normal progress through the cell cycle. Also regulates mitochondrial integrity and function.
• Reactome Pathway:
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)
  RAS processing (R-HSA-9648002)
  Post-chaperonin tubulin folding pathway (R-HSA-389977)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1	DISFHT49	Limited	Autosomal dominant	[1]

7 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 2 (ARL2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[6]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[7]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ADP-ribosylation factor-like protein 2 (ARL2).	[8]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [7] MicroRNA-195 targets ADP-ribosylation factor-like protein 2 to induce apoptosis in human embryonic stem cell-derived neural progenitor cells. Cell Death Dis. 2013 Jun 27;4(6):e695. doi: 10.1038/cddis.2013.195.
• [8] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.