Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3F6ZCB)

• DOT Name: Splicing regulatory glutamine/lysine-rich protein 1 (SREK1)
• Synonyms: Serine/arginine-rich-splicing regulatory protein 86; SRrp86; Splicing factor, arginine/serine-rich 12; Splicing regulatory protein 508; SRrp508
• Gene Name: SREK1
• Related Disease: Alzheimer disease
• UniProt ID: SREK1_HUMAN
• Pfam ID: PF00076
• Sequence:
  MTSLMPGAGLLPIPTPNPLTTLGVSLSSLGAIPAAALDPNIATLGEIPQPPLMGNVDPSK
  IDEIRRTVYVGNLNSQTTTADQLLEFFKQVGEVKFVRMAGDETQPTRFAFVEFADQNSVP
  RALAFNGVMFGDRPLKINHSNNAIVKPPEMTPQAAAKELEEVMKRVREAQSFISAAIEPE
  SGKSNERKGGRSRSHTRSKSRSSSKSHSRRKRSQSKHRSRSHNRSRSRQKDRRRSKSPHK
  KRSKSRERRKSRSRSHSRDKRKDTREKIKEKERVKEKDREKEREREKEREKEKERGKNKD
  RDKEREKDREKDKEKDREREREKEHEKDRDKEKEKEQDKEKEREKDRSKEIDEKRKKDKK
  SRTPPRSYNASRRSRSSSRERRRRRSRSSSRSPRTSKTIKRKSSRSPSPRSRNKKDKKRE
  KERDHISERRERERSTSMRKSSNDRDGKEKLEKNSTSLKEKEHNKEPDSSVSKEVDDKDA
  PRTEENKIQHNGNCQLNEENLSTKTEAV
• Function: Participates in the regulation of alternative splicing by modulating the activity of other splice facors. Inhibits the splicing activity of SFRS1, SFRS2 and SFRS6. Augments the splicing activity of SFRS3.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]

10 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 Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[2]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[7]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[12]

2 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 Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Splicing regulatory glutamine/lysine-rich protein 1 (SREK1).	[9]

References

• [1] The splicing regulatory protein p18SRP is down-regulated in Alzheimer's disease brain.J Mol Neurosci. 2004;24(2):269-76. doi: 10.1385/JMN:24:2:269.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [5] 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.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] 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.
• [9] 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.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [12] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.