Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKWVF8P)

• DOT Name: Actin-related protein 2/3 complex subunit 3 (ARPC3)
• Synonyms: Arp2/3 complex 21 kDa subunit; p21-ARC
• Gene Name: ARPC3
• Related Disease:
  Porokeratosis
  Porokeratosis of Mibelli
  Parkinson disease
  Disseminated superficial actinic porokeratosis
• UniProt ID: ARPC3_HUMAN
• PDB ID: 6UHC; 6YW6; 6YW7
• Pfam ID: PF04062
• Sequence:
  MPAYHSSLMDPDTKLIGNMALLPIRSQFKGPAPRETKDTDIVDEAIYYFKANVFFKNYEI
  KNEADRTLIYITLYISECLKKLQKCNSKSQGEKEMYTLGITNFPIPGEPGFPLNAIYAKP
  ANKQEDEVMRAYLQQLRQETGLRLCEKVFDPQNDKPSKWWTCFVKRQFMNKSLSGPGQ
• Function: Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Tight junction (hsa04530)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Porokeratosis	DISJPL2I	Definitive	Biomarker	[1]
Porokeratosis of Mibelli	DISF48DQ	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Therapeutic	[2]
Disseminated superficial actinic porokeratosis	DISELZ77	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[17]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[12]

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 decreases the methylation of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Actin-related protein 2/3 complex subunit 3 (ARPC3).	[15]

References

• [1] Reassessment of microarray expression data of porokeratosis by quantitative real-time polymerase chain reaction.J Cutan Pathol. 2010 Mar;37(3):371-5. doi: 10.1111/j.1600-0560.2009.01332.x. Epub 2009 Jul 13.
• [2] Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor 1 is enhanced after co-infusion in rats.Exp Neurol. 2010 Nov;226(1):136-47. doi: 10.1016/j.expneurol.2010.08.016. Epub 2010 Aug 14.
• [3] Two closely linked variations in actin cytoskeleton pathway in a Chinese pedigree with disseminated superficial actinic porokeratosis.J Am Acad Dermatol. 2005 Jun;52(6):972-6. doi: 10.1016/j.jaad.2005.01.099.
• [4] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [5] 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.
• [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] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [11] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [12] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [13] 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.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [18] 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.