Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FITK2)

• DOT Name: Heterogeneous nuclear ribonucleoprotein R (HNRNPR)
• Synonyms: hnRNP R
• Gene Name: HNRNPR
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Syndromic intellectual disability
  Advanced cancer
  Brachydactyly
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric cancer
  Intellectual disability
  Neoplasm
  Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities
  Spinal muscular atrophy
  Stomach cancer
  Frontotemporal dementia
  Neuroblastoma
• UniProt ID: HNRPR_HUMAN
• PDB ID: 2DK2
• Pfam ID: PF18360 ; PF00076
• Sequence:
  MANQVNGNAVQLKEEEEPMDTSSVTHTEHYKTLIEAGLPQKVAERLDEIFQTGLVAYVDL
  DERAIDALREFNEEGALSVLQQFKESDLSHVQNKSAFLCGVMKTYRQREKQGSKVQESTK
  GPDEAKIKALLERTGYTLDVTTGQRKYGGPPPDSVYSGVQPGIGTEVFVGKIPRDLYEDE
  LVPLFEKAGPIWDLRLMMDPLSGQNRGYAFITFCGKEAAQEAVKLCDSYEIRPGKHLGVC
  ISVANNRLFVGSIPKNKTKENILEEFSKVTEGLVDVILYHQPDDKKKNRGFCFLEYEDHK
  SAAQARRRLMSGKVKVWGNVVTVEWADPVEEPDPEVMAKVKVLFVRNLATTVTEEILEKS
  FSEFGKLERVKKLKDYAFVHFEDRGAAVKAMDEMNGKEIEGEEIEIVLAKPPDKKRKERQ
  AARQASRSTAYEDYYYHPPPRMPPPIRGRGRGGGRGGYGYPPDYYGYEDYYDDYYGYDYH
  DYRGGYEDPYYGYDDGYAVRGRGGGRGGRGAPPPPRGRGAPPPRGRAGYSQRGAPLGPPR
  GSRGGRGGPAQQQRGRGSRGSRGNRGGNVGGKRKADGYNQPDSKRRQTNNQQNWGSQPIA
  QQPLQQGGDYSGNYGYNNDNQEFYQDTYGQQWK
• Function: Component of ribonucleosomes, which are complexes of at least 20 other different heterogeneous nuclear ribonucleoproteins (hnRNP). hnRNP play an important role in processing of precursor mRNA in the nucleus.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Brachydactyly	DIS2533F	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities	DISLVDTL	Strong	Autosomal dominant	[5]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[7]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[8]

4 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 Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[15]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Heterogeneous nuclear ribonucleoprotein R (HNRNPR).	[24]

References

• [1] HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans. Am J Hum Genet. 2019 Jun 6;104(6):1040-1059. doi: 10.1016/j.ajhg.2019.03.024. Epub 2019 May 9.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.Aging (Albany NY). 2019 Sep 16;11(18):7473-7491. doi: 10.18632/aging.102254. Epub 2019 Sep 16.
• [4] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [5] Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016 Sep;18(9):898-905. doi: 10.1038/gim.2015.186. Epub 2016 Jan 21.
• [6] Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?.Hum Mol Genet. 2002 Jan 1;11(1):93-105. doi: 10.1093/hmg/11.1.93.
• [7] Heterogeneous nuclear ribonucleoproteins R and Q accumulate in pathological inclusions in FTLD-FUS.Acta Neuropathol Commun. 2019 Feb 12;7(1):18. doi: 10.1186/s40478-019-0673-y.
• [8] Systematic Analysis of Gene Expression Profiles Controlled by hnRNP Q and hnRNP R, Two Closely Related Human RNA Binding Proteins Implicated in mRNA Processing Mechanisms.Front Mol Biosci. 2018 Aug 30;5:79. doi: 10.3389/fmolb.2018.00079. eCollection 2018.
• [9] 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.
• [10] 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.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [14] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [15] 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.
• [16] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [17] Benzo[a]pyrene treatment leads to changes in nuclear protein expression and alternative splicing. Mutat Res. 2010 Apr 1;686(1-2):47-56. doi: 10.1016/j.mrfmmm.2010.01.015. Epub 2010 Jan 25.
• [18] 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.
• [19] 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.
• [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] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.