Details of Drug Off-Target (DOT)

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

• DOT Name: Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2)
• Synonyms: EC 2.7.12.1
• Gene Name: DYRK2
• UniProt ID: DYRK2_HUMAN
• PDB ID: 3K2L; 3KVW; 4AZF; 5LXC; 5LXD; 5ZTN; 6HDP; 6HDR; 6K0J; 7AKF; 7AKH; 7DG4; 7DH3; 7DH9; 7DHC; 7DHH; 7DHK; 7DHN; 7DHO; 7DHV; 7DJO; 7DL6
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MLTRKPSAAAPAAYPTGRGGDSAVRQLQASPGLGAGATRSGVGTGPPSPIALPPLRASNA
  AAAAHTIGGSKHTMNDHLHVGSHAHGQIQVQQLFEDNSNKRTVLTTQPNGLTTVGKTGLP
  VVPERQLDSIHRRQGSSTSLKSMEGMGKVKATPMTPEQAMKQYMQKLTAFEHHEIFSYPE
  IYFLGLNAKKRQGMTGGPNNGGYDDDQGSYVQVPHDHVAYRYEVLKVIGKGSFGQVVKAY
  DHKVHQHVALKMVRNEKRFHRQAAEEIRILEHLRKQDKDNTMNVIHMLENFTFRNHICMT
  FELLSMNLYELIKKNKFQGFSLPLVRKFAHSILQCLDALHKNRIIHCDLKPENILLKQQG
  RSGIKVIDFGSSCYEHQRVYTYIQSRFYRAPEVILGARYGMPIDMWSLGCILAELLTGYP
  LLPGEDEGDQLACMIELLGMPSQKLLDASKRAKNFVSSKGYPRYCTVTTLSDGSVVLNGG
  RSRRGKLRGPPESREWGNALKGCDDPLFLDFLKQCLEWDPAVRMTPGQALRHPWLRRRLP
  KPPTGEKTSVKRITESTGAITSISKLPPPSSSASKLRTNLAQMTDANGNIQQRTVLPKLV
  S
• Function: Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).
• Tissue Specificity: Testis, after the onset of spermatogenesis.
• Reactome Pathway: Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)

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
Mitoxantrone	DMM39BF	Approved	Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) affects the response to substance of Mitoxantrone.	[17]

20 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 tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[11]
Mestranol	DMG3F94	Approved	Mestranol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	[14]

References

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• [2] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [6] 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.
• [7] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative. J Biol Chem. 2021 Jan-Jun;296:100449. doi: 10.1016/j.jbc.2021.100449. Epub 2021 Feb 20.
• [14] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [15] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [16] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.