Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLI7CU1)

• DOT Name: Serine/arginine-rich splicing factor 4 (SRSF4)
• Synonyms: Pre-mRNA-splicing factor SRP75; SRP001LB; Splicing factor, arginine/serine-rich 4
• Gene Name: SRSF4
• Related Disease:
  Adrenoleukodystrophy
  Frontotemporal dementia
  Hepatitis B virus infection
  Hepatitis C virus infection
  Neoplasm
  Pick disease
• UniProt ID: SRSF4_HUMAN
• Pfam ID: PF00076
• Sequence:
  MPRVYIGRLSYQARERDVERFFKGYGKILEVDLKNGYGFVEFDDLRDADDAVYELNGKDL
  CGERVIVEHARGPRRDGSYGSGRSGYGYRRSGRDKYGPPTRTEYRLIVENLSSRCSWQDL
  KDYMRQAGEVTYADAHKGRKNEGVIEFVSYSDMKRALEKLDGTEVNGRKIRLVEDKPGSR
  RRRSYSRSRSHSRSRSRSRHSRKSRSRSGSSKSSHSKSRSRSRSGSRSRSKSRSRSQSRS
  RSKKEKSRSPSKEKSRSRSHSAGKSRSKSKDQAEEKIQNNDNVGKPKSRSPSRHKSKSKS
  RSRSQERRVEEEKRGSVSRGRSQEKSLRQSRSRSRSKGGSRSRSRSRSKSKDKRKGRKRS
  REESRSRSRSRSKSERSRKRGSKRDSKAGSSKKKKKEDTDRSQSRSPSRSVSKEREHAKS
  ESSQREGRGESENAGTNQETRSRSRSNSKSKPNLPSESRSRSKSASKTRSRSKSRSRSAS
  RSPSRSRSRSHSRS
• Function: Plays a role in alternative splice site selection during pre-mRNA splicing. Represses the splicing of MAPT/Tau exon 10.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenoleukodystrophy	DISTUD1F	Strong	Biomarker	[1]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pick disease	DISP6X50	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[13]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[13]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Serine/arginine-rich splicing factor 4 (SRSF4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Serine/arginine-rich splicing factor 4 (SRSF4).	[8]

5 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 Serine/arginine-rich splicing factor 4 (SRSF4).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Serine/arginine-rich splicing factor 4 (SRSF4).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/arginine-rich splicing factor 4 (SRSF4).	[12]
Paraquat	DMR8O3X	Investigative	Paraquat increases the phosphorylation of Serine/arginine-rich splicing factor 4 (SRSF4).	[14]
leucettine L41	DMBYND6	Investigative	leucettine L41 decreases the phosphorylation of Serine/arginine-rich splicing factor 4 (SRSF4).	[15]

References

• [1] Housekeeping gene variability in the liver of alcoholic patients.Alcohol Clin Exp Res. 2012 Feb;36(2):258-66. doi: 10.1111/j.1530-0277.2011.01627.x. Epub 2011 Sep 13.
• [2] An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia.Gene. 2011 Oct 10;485(2):130-8. doi: 10.1016/j.gene.2011.06.020. Epub 2011 Jun 30.
• [3] Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver.J Viral Hepat. 2011 Jan;18(1):53-60. doi: 10.1111/j.1365-2893.2010.01283.x.
• [4] RON alternative splicing regulation in primary ovarian cancer.Oncol Rep. 2015 Jul;34(1):423-30. doi: 10.3892/or.2015.3995. Epub 2015 May 19.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [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] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [9] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [14] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [15] Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem. 2011 Jun 23;54(12):4172-86.