Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO7O3CU)

• DOT Name: Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B)
• Synonyms: EC 2.7.12.1; Minibrain-related kinase; Mirk protein kinase
• Gene Name: DYRK1B
• Related Disease: Abdominal obesity-metabolic syndrome 3
• UniProt ID: DYR1B_HUMAN
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MAVPPGHGPFSGFPGPQEHTQVLPDVRLLPRRLPLAFRDATSAPLRKLSVDLIKTYKHIN
  EVYYAKKKRRAQQAPPQDSSNKKEKKVLNHGYDDDNHDYIVRSGERWLERYEIDSLIGKG
  SFGQVVKAYDHQTQELVAIKIIKNKKAFLNQAQIELRLLELMNQHDTEMKYYIVHLKRHF
  MFRNHLCLVFELLSYNLYDLLRNTHFRGVSLNLTRKLAQQLCTALLFLATPELSIIHCDL
  KPENILLCNPKRSAIKIVDFGSSCQLGQRIYQYIQSRFYRSPEVLLGTPYDLAIDMWSLG
  CILVEMHTGEPLFSGSNEVDQMNRIVEVLGIPPAAMLDQAPKARKYFERLPGGGWTLRRT
  KELRKDYQGPGTRRLQEVLGVQTGGPGGRRAGEPGHSPADYLRFQDLVLRMLEYEPAARI
  SPLGALQHGFFRRTADEATNTGPAGSSASTSPAPLDTCPSSSTASSISSSGGSSGSSSDN
  RTYRYSNRYCGGPGPPITDCEMNSPQVPPSQPLRPWAGGDVPHKTHQAPASASSLPGTGA
  QLPPQPRYLGRPPSPTSPPPPELMDVSLVGGPADCSPPHPAPAPQHPAASALRTRMTGGR
  PPLPPPDDPATLGPHLGLRGVPQSTAASS
• Function: Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Plays an essential role in ribosomal DNA (rDNA) double-strand break repair and rDNA copy number maintenance. During DNA damage, mediates transcription silencing in part via phosphorylating and enforcing DSB accumulation of the histone methyltransferase EHMT2. Enhances the transcriptional activity of TCF1/HNF1A and FOXO1. Inhibits epithelial cell migration. Mediates colon carcinoma cell survival in mitogen-poor environments. Inhibits the SHH and WNT1 pathways, thereby enhancing adipogenesis. In addition, promotes expression of the gluconeogenic enzyme glucose-6-phosphatase catalytic subunit 1 (G6PC1).
• Tissue Specificity: Highest expression in skeletal muscle, testis, heart and brain with little expression in colon or lung. Expressed in a variety of tumor cell lines.
• BioCyc Pathway: MetaCyc:HS02690-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abdominal obesity-metabolic syndrome 3	DISP424Q	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) affects the response to substance of Temozolomide.	[13]
DTI-015	DMXZRW0	Approved	Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) affects the response to substance of DTI-015.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[10]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B).	[12]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.