Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC33Y2F)

• DOT Name: Serine/threonine-protein kinase 10 (STK10)
• Synonyms: EC 2.7.11.1; Lymphocyte-oriented kinase
• Gene Name: STK10
• Related Disease:
  Dermatitis
  Neoplasm
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Asthma
  Hepatocellular carcinoma
  Testicular germ cell tumor
• UniProt ID: STK10_HUMAN
• PDB ID: 2J7T; 4AOT; 4BC6; 4EQU; 4USD; 4USE; 5AJQ; 5OWQ; 5OWR; 6EIM; 6GTT; 6HXF; 6I2Y; 7QGP
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF12474
• Sequence:
  MAFANFRRILRLSTFEKRKSREYEHVRRDLDPNEVWEIVGELGDGAFGKVYKAKNKETGA
  LAAAKVIETKSEEELEDYIVEIEILATCDHPYIVKLLGAYYHDGKLWIMIEFCPGGAVDA
  IMLELDRGLTEPQIQVVCRQMLEALNFLHSKRIIHRDLKAGNVLMTLEGDIRLADFGVSA
  KNLKTLQKRDSFIGTPYWMAPEVVMCETMKDTPYDYKADIWSLGITLIEMAQIEPPHHEL
  NPMRVLLKIAKSDPPTLLTPSKWSVEFRDFLKIALDKNPETRPSAAQLLEHPFVSSITSN
  KALRELVAEAKAEVMEEIEDGRDEGEEEDAVDAASTLENHTQNSSEVSPPSLNADKPLEE
  SPSTPLAPSQSQDSVNEPCSQPSGDRSLQTTSPPVVAPGNENGLAVPVPLRKSRPVSMDA
  RIQVAQEKQVAEQGGDLSPAANRSQKASQSRPNSSALETLGGEKLANGSLEPPAQAAPGP
  SKRDSDCSSLCTSESMDYGTNLSTDLSLNKEMGSLSIKDPKLYKKTLKRTRKFVVDGVEV
  SITTSKIISEDEKKDEEMRFLRRQELRELRLLQKEEHRNQTQLSNKHELQLEQMHKRFEQ
  EINAKKKFFDTELENLERQQKQQVEKMEQDHAVRRREEARRIRLEQDRDYTRFQEQLKLM
  KKEVKNEVEKLPRQQRKESMKQKMEEHTQKKQLLDRDFVAKQKEDLELAMKRLTTDNRRE
  ICDKERECLMKKQELLRDREAALWEMEEHQLQERHQLVKQQLKDQYFLQRHELLRKHEKE
  REQMQRYNQRMIEQLKVRQQQEKARLPKIQRSEGKTRMAMYKKSLHINGGGSAAEQREKI
  KQFSQQEEKRQKSERLQQQQKHENQMRDMLAQCESNMSELQQLQNEKCHLLVEHETQKLK
  ALDESHNQNLKEWRDKLRPRKKALEEDLNQKKREQEMFFKLSEEAECPNPSTPSKAAKFF
  PYSSADAS
• Function: Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo.
• Tissue Specificity: Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung.
• KEGG Pathway: Progesterone-mediated oocyte maturation (hsa04914)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dermatitis	DISY5SZC	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Genetic Variation	[2]
Asthma	DISW9QNS	moderate	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[4]
Testicular germ cell tumor	DIS5RN24	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Serine/threonine-protein kinase 10 (STK10) affects the response to substance of Aspirin.	[3]

12 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/threonine-protein kinase 10 (STK10).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase 10 (STK10).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase 10 (STK10).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase 10 (STK10).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase 10 (STK10).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein kinase 10 (STK10).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/threonine-protein kinase 10 (STK10).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Serine/threonine-protein kinase 10 (STK10).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase 10 (STK10).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein kinase 10 (STK10).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase 10 (STK10).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein kinase 10 (STK10).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein kinase 10 (STK10).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Serine/threonine-protein kinase 10 (STK10).	[17]

References

• [1] Off-target serine/threonine kinase 10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders.Mol Pharmacol. 2011 Sep;80(3):466-75. doi: 10.1124/mol.110.070862. Epub 2011 May 23.
• [2] STK10 missense mutations associated with anti-apoptotic function.Oncol Rep. 2013 Oct;30(4):1542-8. doi: 10.3892/or.2013.2605. Epub 2013 Jul 9.
• [3] Variations in the STK10 gene and possible associations with aspirin-intolerant asthma in a Korean population. J Investig Allergol Clin Immunol. 2011;21(5):378-88.
• [4] Fibro markers for prediction of hepatocellular carcinoma in Egyptian patients with chronic liver disease.J Med Virol. 2017 Jun;89(6):1062-1068. doi: 10.1002/jmv.24720. Epub 2016 Dec 9.
• [5] Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults.Genes Chromosomes Cancer. 2006 Jan;45(1):42-6. doi: 10.1002/gcc.20265.
• [6] 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.
• [7] 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.
• [8] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Variations in the STK10 gene and possible associations with aspirin-intolerant asthma in a Korean population. J Investig Allergol Clin Immunol. 2011;21(5):378-88.