Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5GO2PL)

• DOT Name: KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1)
• Synonyms: GAP-associated tyrosine phosphoprotein p62; Src-associated in mitosis 68 kDa protein; Sam68; p21 Ras GTPase-activating protein-associated p62; p68
• Gene Name: KHDRBS1
• UniProt ID: KHDR1_HUMAN
• PDB ID: 2XA6; 3QHE; 7Z89; 7Z9A; 7ZAB; 7ZAM
• Pfam ID: PF00013 ; PF16274 ; PF16568
• Sequence:
  MQRRDDPAARMSRSSGRSGSMDPSGAHPSVRQTPSRQPPLPHRSRGGGGGSRGGARASPA
  TQPPPLLPPSATGPDATVGGPAPTPLLPPSATASVKMEPENKYLPELMAEKDSLDPSFTH
  AMQLLTAEIEKIQKGDSKKDDEENYLDLFSHKNMKLKERVLIPVKQYPKFNFVGKILGPQ
  GNTIKRLQEETGAKISVLGKGSMRDKAKEEELRKGGDPKYAHLNMDLHVFIEVFGPPCEA
  YALMAHAMEEVKKFLVPDMMDDICQEQFLELSYLNGVPEPSRGRGVPVRGRGAAPPPPPV
  PRGRGVGPPRGALVRGTPVRGAITRGATVTRGVPPPPTVRGAPAPRARTAGIQRIPLPPP
  PAPETYEEYGYDDTYAEQSYEGYEGYYSQSQGDSEYYDYGHGEVQDSYEAYGQDDWNGTR
  PSLKAPPARPVKGAYREHPYGRY
• Function: Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors. Once phosphorylated, functions as an adapter protein in signal transduction cascades by binding to SH2 and SH3 domain-containing proteins. Role in G2-M progression in the cell cycle. Represses CBP-dependent transcriptional activation apparently by competing with other nuclear factors for binding to CBP. Also acts as a putative regulator of mRNA stability and/or translation rates and mediates mRNA nuclear export. Positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. According to some authors, is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species according to. RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). Can regulate CD44 alternative splicing in a Ras pathway-dependent manner. In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1. Can regulate alternative splicing of NRXN1 and NRXN3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. In a neuronal activity-dependent manner cooperates synergistically with KHDRBS2/SLIM-1 in regulation of NRXN1 exon skipping at AS4. The cooperation with KHDRBS2/SLIM-1 is antagonistic for regulation of NXRN3 alternative splicing at AS4; Isoform 3, which is expressed in growth-arrested cells only, inhibits S phase.
• Tissue Specificity: Ubiquitously expressed in all tissue examined. Isoform 1 is expressed at lower levels in brain, skeletal muscle, and liver whereas isoform 3 is intensified in skeletal muscle and in liver.
• Reactome Pathway: PTK6 Regulates Proteins Involved in RNA Processing (R-HSA-8849468)

Molecular Interaction Atlas (MIA) of This DOT

18 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 KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[9]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[10]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[11]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[18]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[19]

3 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 KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRBS1).	[15]

References

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• [3] 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.
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• [6] 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.
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• [11] 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.
• [12] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [13] 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.
• [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] 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.
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• [18] 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.
• [19] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.