Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4YAFUS)

• DOT Name: PC4 and SFRS1-interacting protein (PSIP1)
• Synonyms: CLL-associated antigen KW-7; Dense fine speckles 70 kDa protein; DFS 70; Lens epithelium-derived growth factor; Transcriptional coactivator p75/p52
• Gene Name: PSIP1
• UniProt ID: PSIP1_HUMAN
• PDB ID: 1Z9E; 2B4J; 2M16; 2MSR; 2MTN; 2N3A; 3F9K; 3HPG; 3HPH; 3U88; 3ZEH; 4FU6; 5N88; 5OYM; 5YI9; 6EMO; 6EMP; 6EMQ; 6EMR; 6S01; 6TRJ; 6TVM; 6ZV0; 7OUF; 7OUG; 7OUH; 7PEL; 7Z1Z; 8CBQ; 8PC5; 8PC6; 8PEO; 8PEP
• Pfam ID: PF11467 ; PF00855
• Sequence:
  MTRDFKPGDLIFAKMKGYPHWPARVDEVPDGAVKPPTNKLPIFFFGTHETAFLGPKDIFP
  YSENKEKYGKPNKRKGFNEGLWEIDNNPKVKFSSQQAATKQSNASSDVEVEEKETSVSKE
  DTDHEEKASNEDVTKAVDITTPKAARRGRKRKAEKQVETEEAGVVTTATASVNLKVSPKR
  GRPAATEVKIPKPRGRPKMVKQPCPSESDIITEEDKSKKKGQEEKQPKKQPKKDEEGQKE
  EDKPRKEPDKKEGKKEVESKRKNLAKTGVTSTSDSEEEGDDQEGEKKRKGGRNFQTAHRR
  NMLKGQHEKEAADRKRKQEEQMETEQQNKDEGKKPEVKKVEKKRETSMDSRLQRIHAEIK
  NSLKIDNLDVNRCIEALDELASLQVTMQQAQKHTEMITTLKKIRRFKVSQVIMEKSTMLY
  NKFKNMFLVGEGDSVITQVLNKSLAEQRQHEEANKTKDQGKKGPNKKLEKEQTGSKTLNG
  GSDAQDGNQPQHNGESNEDSKDNHEASTKKKPSSEERETEISLKDSTLDN
• Function: Transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Involved in particular in lens epithelial cell gene regulation and stress responses. May play an important role in lens epithelial to fiber cell terminal differentiation. May play a protective role during stress-induced apoptosis. Isoform 2 is a more general and stronger transcriptional coactivator. Isoform 2 may also act as an adapter to coordinate pre-mRNA splicing. Cellular cofactor for lentiviral integration.
• Tissue Specificity: Widely expressed. Expressed at high level in the thymus. Expressed in fetal and adult brain. Expressed in neurons, but not astrocytes. Markedly elevated in fetal as compared to adult brain. In the adult brain, expressed in the subventricular zone (SVZ), in hippocampus, and undetectable elsewhere. In the fetal brain, expressed in the germinal neuroepithelium and cortical plate regions.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  2-LTR circle formation (R-HSA-164843)
  Integration of viral DNA into host genomic DNA (R-HSA-175567)
  Autointegration results in viral DNA circles (R-HSA-177539)
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Integration of provirus (R-HSA-162592)

Molecular Interaction Atlas (MIA) of This DOT

16 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 PC4 and SFRS1-interacting protein (PSIP1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of PC4 and SFRS1-interacting protein (PSIP1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of PC4 and SFRS1-interacting protein (PSIP1).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of PC4 and SFRS1-interacting protein (PSIP1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of PC4 and SFRS1-interacting protein (PSIP1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of PC4 and SFRS1-interacting protein (PSIP1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Docetaxel	DMDI269	Approved	Docetaxel increases the cleavage of PC4 and SFRS1-interacting protein (PSIP1).	[12]

References

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• [2] 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.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [12] Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Mol Cancer. 2009 Aug 28;8:68. doi: 10.1186/1476-4598-8-68.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.