Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXTV6FU)

• DOT Name: Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A)
• Synonyms: Cyclin-dependent kinase inhibitor 2B-related protein; p15INK4B-related protein
• Gene Name: RPRD1A
• Related Disease:
  Neoplasm
  Advanced cancer
  Breast cancer
  Metastatic melanoma
  Breast carcinoma
• UniProt ID: RPR1A_HUMAN
• PDB ID: 4JXT; 4NAC
• Pfam ID: PF04818 ; PF16566
• Sequence:
  MSAFSEAALEKKLSELSNSQQSVQTLSLWLIHHRKHSRPIVTVWERELRKAKPNRKLTFL
  YLANDVIQNSKRKGPEFTKDFAPVIVEAFKHVSSETDESCKKHLGRVLSIWEERSVYEND
  VLEQLKQALYGDKKPRKRTYEQIKVDENENCSSLGSPSEPPQTLDLVRALQDLENAASGD
  AAVHQRIASLPVEVQEVSLLDKITDKESGERLSKMVEDACMLLADYNGRLAAEIDDRKQL
  TRMLADFLRCQKEALAEKEHKLEEYKRKLARVSLVRKELRSRIQSLPDLSRLPNVTGSHM
  HLPFAGDIYSED
• Function: Interacts with phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and participates in dephosphorylation of the CTD by RPAP2. May act as a negative regulator of cyclin-D1 (CCND1) and cyclin-E (CCNE1) in the cell cycle.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[3]

13 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 Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A).	[15]

References

• [1] Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.J Biol Chem. 2018 May 18;293(20):7618-7628. doi: 10.1074/jbc.RA118.001969. Epub 2018 Apr 4.
• [2] Cellular and molecular evidence for malignancy-inhibitory functions of p15RS.Cell Cycle. 2012 May 15;11(10):1988-98. doi: 10.4161/cc.20400. Epub 2012 May 15.
• [3] MiR-454-3p-Mediated Wnt/-catenin Signaling Antagonists Suppression Promotes Breast Cancer Metastasis.Theranostics. 2019 Jan 1;9(2):449-465. doi: 10.7150/thno.29055. eCollection 2019.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] 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.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.