Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG1LACW)

• DOT Name: Dual specificity protein kinase CLK1 (CLK1)
• Synonyms: EC 2.7.12.1; CDC-like kinase 1
• Gene Name: CLK1
• UniProt ID: CLK1_HUMAN
• PDB ID: 1Z57 ; 2VAG ; 5J1V ; 5J1W ; 5X8I ; 6FT8 ; 6FT9 ; 6FYO ; 6G33 ; 6I5H ; 6I5I ; 6I5K ; 6I5L ; 6KHD ; 6Q8K ; 6Q8P ; 6QTY ; 6R3D ; 6R6E ; 6R6X ; 6R8J ; 6RAA ; 6TW2 ; 6YTA ; 6YTD ; 6YTE ; 6YTG ; 6YTI ; 6Z4Z ; 6Z50 ; 6ZLN ; 7AK3 ; 7O9Y ; 7OA0 ; 7OPG ; 8P04 ; 8P08
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MRHSKRTYCPDWDDKDWDYGKWRSSSSHKRRKRSHSSAQENKRCKYNHSKMCDSHYLESR
  SINEKDYHSRRYIDEYRNDYTQGCEPGHRQRDHESRYQNHSSKSSGRSGRSSYKSKHRIH
  HSTSHRRSHGKSHRRKRTRSVEDDEEGHLICQSGDVLSARYEIVDTLGEGAFGKVVECID
  HKAGGRHVAVKIVKNVDRYCEAARSEIQVLEHLNTTDPNSTFRCVQMLEWFEHHGHICIV
  FELLGLSTYDFIKENGFLPFRLDHIRKMAYQICKSVNFLHSNKLTHTDLKPENILFVQSD
  YTEAYNPKIKRDERTLINPDIKVVDFGSATYDDEHHSTLVSTRHYRAPEVILALGWSQPC
  DVWSIGCILIEYYLGFTVFPTHDSKEHLAMMERILGPLPKHMIQKTRKRKYFHHDRLDWD
  EHSSAGRYVSRRCKPLKEFMLSQDVEHERLFDLIQKMLEYDPAKRITLREALKHPFFDLL
  KKSI
• Function: Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.
• Tissue Specificity: Endothelial cells.
• KEGG Pathway: Legionellosis (hsa05134)

Molecular Interaction Atlas (MIA) of This DOT

22 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 Dual specificity protein kinase CLK1 (CLK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dual specificity protein kinase CLK1 (CLK1).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Dual specificity protein kinase CLK1 (CLK1).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[20]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[21]
PATULIN	DM0RV9C	Investigative	PATULIN decreases the expression of Dual specificity protein kinase CLK1 (CLK1).	[22]
GW7604	DMCA4RM	Investigative	GW7604 increases the expression of Dual specificity protein kinase CLK1 (CLK1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Dual specificity protein kinase CLK1 (CLK1).	[17]

References

• [1] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [7] 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.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res. 2002 Aug 1;62(15):4419-26.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] 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.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [20] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [21] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [22] Patulin transformation products and last intermediates in its biosynthetic pathway, E- and Z-ascladiol, are not toxic to human cells. Arch Toxicol. 2017 Jun;91(6):2455-2467. doi: 10.1007/s00204-016-1900-y. Epub 2016 Dec 2.