Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4O4NFS)

• DOT Name: Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3)
• Synonyms: hnRNP A3
• Gene Name: HNRNPA3
• Related Disease:
  Motor neurone disease
  Multiple endocrine neoplasia type 2A
  Schizophrenia
  Lung neoplasm
  Amyotrophic lateral sclerosis
  Familial medullary thyroid carcinoma
  Medullary thyroid gland carcinoma
  Multiple endocrine neoplasia type 2
• UniProt ID: ROA3_HUMAN
• Pfam ID: PF00076
• Sequence:
  MEVKPPPGRPQPDSGRRRRRRGEEGHDPKEPEQLRKLFIGGLSFETTDDSLREHFEKWGT
  LTDCVVMRDPQTKRSRGFGFVTYSCVEEVDAAMCARPHKVDGRVVEPKRAVSREDSVKPG
  AHLTVKKIFVGGIKEDTEEYNLRDYFEKYGKIETIEVMEDRQSGKKRGFAFVTFDDHDTV
  DKIVVQKYHTINGHNCEVKKALSKQEMQSAGSQRGRGGGSGNFMGRGGNFGGGGGNFGRG
  GNFGGRGGYGGGGGGSRGSYGGGDGGYNGFGGDGGNYGGGPGYSSRGGYGGGGPGYGNQG
  GGYGGGGGYDGYNEGGNFGGGNYGGGGNYNDFGNYSGQQQSNYGPMKGGSFGGRSSGSPY
  GGGYGSGGGSGGYGSRRF
• Function: Plays a role in cytoplasmic trafficking of RNA. Binds to the cis-acting response element, A2RE. May be involved in pre-mRNA splicing.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Motor neurone disease	DISUHWUI	Strong	Biomarker	[1]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	moderate	Altered Expression	[4]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[5]
Familial medullary thyroid carcinoma	DIS01PWX	Limited	Genetic Variation	[2]
Medullary thyroid gland carcinoma	DISHBL3K	Limited	Genetic Variation	[2]
Multiple endocrine neoplasia type 2	DISPQ4Y5	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[14]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[16]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[18]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3).	[20]

References

• [1] Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene.Acta Neuropathol Commun. 2017 Apr 21;5(1):31. doi: 10.1186/s40478-017-0437-5.
• [2] A 1.5-megabase yeast artificial chromosome contig from human chromosome 10q11.2 connecting three genetic loci (RET, D10S94, and D10S102) closely linked to the MEN2A locus.Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):492-6. doi: 10.1073/pnas.90.2.492.
• [3] Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia.Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15533-8. doi: 10.1073/pnas.0507666102. Epub 2005 Oct 13.
• [4] Transcriptional analysis of hnRNPA0, A1, A2, B1, and A3 in lung cancer cell lines in response to acidosis, hypoxia, and serum deprivation conditions.Exp Lung Res. 2014 Feb;40(1):12-21. doi: 10.3109/01902148.2013.856049. Epub 2013 Nov 18.
• [5] Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis.Neurodegener Dis. 2017;17(6):304-312. doi: 10.1159/000481258. Epub 2017 Nov 11.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [18] 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.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] 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.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.