Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP03OD0)

• DOT Name: Tyrosine-protein kinase CSK (CSK)
• Synonyms: EC 2.7.10.2; C-Src kinase; Protein-tyrosine kinase CYL
• Gene Name: CSK
• UniProt ID: CSK_HUMAN
• PDB ID: 1BYG; 1CSK; 3D7T; 3D7U; 3EAC; 3EAZ
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MSAIQAAWPSGTECIAKYNFHGTAEQDLPFCKGDVLTIVAVTKDPNWYKAKNKVGREGII
  PANYVQKREGVKAGTKLSLMPWFHGKITREQAERLLYPPETGLFLVRESTNYPGDYTLCV
  SCDGKVEHYRIMYHASKLSIDEEVYFENLMQLVEHYTSDADGLCTRLIKPKVMEGTVAAQ
  DEFYRSGWALNMKELKLLQTIGKGEFGDVMLGDYRGNKVAVKCIKNDATAQAFLAEASVM
  TQLRHSNLVQLLGVIVEEKGGLYIVTEYMAKGSLVDYLRSRGRSVLGGDCLLKFSLDVCE
  AMEYLEGNNFVHRDLAARNVLVSEDNVAKVSDFGLTKEASSTQDTGKLPVKWTAPEALRE
  KKFSTKSDVWSFGILLWEIYSFGRVPYPRIPLKDVVPRVEKGYKMDAPDGCPPAVYEVMK
  NCWHLDAAMRPSFLQLREQLEHIKTHELHL
• Function: Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.
• Tissue Specificity: Expressed in lung and macrophages.
• KEGG Pathway: Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
• Reactome Pathway:
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)
  Integrin signaling (R-HSA-354192)
  PD-1 signaling (R-HSA-389948)
  MAP2K and MAPK activation (R-HSA-5674135)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  RHOH GTPase cycle (R-HSA-9013407)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  Negative regulation of FLT3 (R-HSA-9706369)
  GAB1 signalosome (R-HSA-180292)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Urokinase	DM0GOUD	Approved	Tyrosine-protein kinase CSK (CSK) increases the Chromosomal abnormalities and abnormal gene carriers ADR of Urokinase.	[22]

19 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 Tyrosine-protein kinase CSK (CSK).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase CSK (CSK).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein kinase CSK (CSK).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine-protein kinase CSK (CSK).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine-protein kinase CSK (CSK).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tyrosine-protein kinase CSK (CSK).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tyrosine-protein kinase CSK (CSK).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tyrosine-protein kinase CSK (CSK).	[10]
Saracatinib	DMBLHGP	Phase 2	Saracatinib decreases the activity of Tyrosine-protein kinase CSK (CSK).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tyrosine-protein kinase CSK (CSK).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase CSK (CSK).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase CSK (CSK).	[13]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase CSK (CSK).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine-protein kinase CSK (CSK).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tyrosine-protein kinase CSK (CSK).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tyrosine-protein kinase CSK (CSK).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Tyrosine-protein kinase CSK (CSK).	[19]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the activity of Tyrosine-protein kinase CSK (CSK).	[20]
Purvalanol A	DMNQ7TM	Investigative	Purvalanol A decreases the activity of Tyrosine-protein kinase CSK (CSK).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the phosphorylation of Tyrosine-protein kinase CSK (CSK).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Tyrosine-protein kinase CSK (CSK).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib affects the binding of Tyrosine-protein kinase CSK (CSK).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] A novel bile acid-activated vitamin D receptor signaling in human hepatocytes. Mol Endocrinol. 2010 Jun;24(6):1151-64.
• [7] 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.
• [8] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [9] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [10] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [11] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] 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.
• [15] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Roles of cytosolic phospholipase A2 and Src kinase in the early action of 2,3,7,8-tetrachlorodibenzo-p-dioxin through a nongenomic pathway in MCF10A cells. Mol Pharmacol. 2008 Jul;74(1):255-63.
• [21] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [22] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.