Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK0XRQN)

• DOT Name: U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4)
• Synonyms: PRP4 homolog; hPrp4; U4/U6 snRNP 60 kDa protein; WD splicing factor Prp4
• Gene Name: PRPF4
• Related Disease:
  Retinitis pigmentosa 70
  Adult teratoma
  Colorectal carcinoma
  Drug dependence
  Hepatocellular carcinoma
  Substance abuse
  Substance dependence
  Teratoma
  Breast cancer
  Breast carcinoma
  Retinitis pigmentosa
• UniProt ID: PRP4_HUMAN
• PDB ID: 1MZW; 3JCR; 5O9Z; 6AH0; 6AHD; 6QW6; 6QX9
• Pfam ID: PF08799 ; PF00400
• Sequence:
  MASSRASSTQATKTKAPDDLVAPVVKKPHIYYGSLEEKERERLAKGESGILGKDGLKAGI
  EAGNINITSGEVFEIEEHISERQAEVLAEFERRKRARQINVSTDDSEVKACLRALGEPIT
  LFGEGPAERRERLRNILSVVGTDALKKTKKDDEKSKKSKEEYQQTWYHEGPNSLKVARLW
  IANYSLPRAMKRLEEARLHKEIPETTRTSQMQELHKSLRSLNNFCSQIGDDRPISYCHFS
  PNSKMLATACWSGLCKLWSVPDCNLLHTLRGHNTNVGAIVFHPKSTVSLDPKDVNLASCA
  ADGSVKLWSLDSDEPVADIEGHTVRVARVMWHPSGRFLGTTCYDRSWRLWDLEAQEEILH
  QEGHSMGVYDIAFHQDGSLAGTGGLDAFGRVWDLRTGRCIMFLEGHLKEIYGINFSPNGY
  HIATGSGDNTCKVWDLRQRRCVYTIPAHQNLVTGVKFEPIHGNFLLTGAYDNTAKIWTHP
  GWSPLKTLAGHEGKVMGLDISSDGQLIATCSYDRTFKLWMAE
• Function: Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 70	DIS84K4C	Definitive	Autosomal dominant	[1]
Adult teratoma	DISBY81U	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Substance abuse	DIS327VW	Strong	Biomarker	[4]
Substance dependence	DISDRAAR	Strong	Biomarker	[4]
Teratoma	DIS6ICY4	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[6]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[11]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[10]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[15]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[16]

1 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 increases the sumoylation of U4/U6 small nuclear ribonucleoprotein Prp4 (PRPF4).	[13]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Suppression of PRPF4 regulates pluripotency, proliferation, and differentiation in mouse embryonic stem cells.Cell Biochem Funct. 2019 Dec;37(8):608-617. doi: 10.1002/cbf.3437. Epub 2019 Sep 10.
• [3] Curcumin induces apoptosis in human colorectal carcinoma (HCT-15) cells by regulating expression of Prp4 and p53.Mol Cells. 2013 Jun;35(6):526-32. doi: 10.1007/s10059-013-0038-5. Epub 2013 May 16.
• [4] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [5] miR-371-5p down-regulates pre mRNA processing factor 4 homolog B (PRPF4B) and facilitates the G1/S transition in human hepatocellular carcinoma cells.Cancer Lett. 2013 Jul 28;335(2):351-60. doi: 10.1016/j.canlet.2013.02.045. Epub 2013 Mar 4.
• [6] PRPF4 is a novel therapeutic target for the treatment of breast cancer by influencing growth, migration, invasion, and apoptosis of breast cancer cells via p38 MAPK signaling pathway.Mol Cell Probes. 2019 Oct;47:101440. doi: 10.1016/j.mcp.2019.101440. Epub 2019 Aug 22.
• [7] PRPF4 mutations cause autosomal dominant retinitis pigmentosa. Hum Mol Genet. 2014 Jun 1;23(11):2926-39. doi: 10.1093/hmg/ddu005. Epub 2014 Jan 12.
• [8] 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.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [13] 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.
• [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] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
• [16] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.