Details of Drug Off-Target (DOT)

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

• DOT Name: Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)
• Synonyms: EC 2.7.11.23; EC 2.7.12.1; Dual specificity YAK1-related kinase; HP86; Protein kinase minibrain homolog; MNBH; hMNB
• Gene Name: DYRK1A
• Related Disease:
  Complex neurodevelopmental disorder
  DYRK1A-related intellectual disability syndrome
• UniProt ID: DYR1A_HUMAN
• PDB ID: 2VX3 ; 2WO6 ; 3ANQ ; 3ANR ; 4AZE ; 4MQ1 ; 4MQ2 ; 4NCT ; 4YLJ ; 4YLK ; 4YLL ; 4YU2 ; 5A3X ; 5A4E ; 5A4L ; 5A4Q ; 5A4T ; 5A54 ; 5AIK ; 6A1F ; 6A1G ; 6EIF ; 6EIJ ; 6EIL ; 6EIP ; 6EIQ ; 6EIR ; 6EIS ; 6EIV ; 6EJ4 ; 6LN1 ; 6QU2 ; 6S11 ; 6S14 ; 6S17 ; 6S1B ; 6S1H ; 6S1I ; 6S1J ; 6T6A ; 6UIP ; 6UWY ; 6YF8 ; 7A4O ; 7A4R ; 7A4S ; 7A4W ; 7A4Z ; 7A51 ; 7A52 ; 7A53 ; 7A55 ; 7A5B ; 7A5D ; 7A5L ; 7A5N ; 7AJ2 ; 7AJ4 ; 7AJ5 ; 7AJ7 ; 7AJ8 ; 7AJA ; 7AJM ; 7AJS ; 7AJV ; 7AJW ; 7AJY ; 7AK2 ; 7AKA ; 7AKB ; 7AKE ; 7AKL ; 7FHS ; 7FHT ; 7O7K ; 7OY6 ; 7Z5N ; 7ZH8
• EC Number: 2.7.11.23; 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MHTGGETSACKPSSVRLAPSFSFHAAGLQMAGQMPHSHQYSDRRQPNISDQQVSALSYSD
  QIQQPLTNQVMPDIVMLQRRMPQTFRDPATAPLRKLSVDLIKTYKHINEVYYAKKKRRHQ
  QGQGDDSSHKKERKVYNDGYDDDNYDYIVKNGEKWMDRYEIDSLIGKGSFGQVVKAYDRV
  EQEWVAIKIIKNKKAFLNQAQIEVRLLELMNKHDTEMKYYIVHLKRHFMFRNHLCLVFEM
  LSYNLYDLLRNTNFRGVSLNLTRKFAQQMCTALLFLATPELSIIHCDLKPENILLCNPKR
  SAIKIVDFGSSCQLGQRIYQYIQSRFYRSPEVLLGMPYDLAIDMWSLGCILVEMHTGEPL
  FSGANEVDQMNKIVEVLGIPPAHILDQAPKARKFFEKLPDGTWNLKKTKDGKREYKPPGT
  RKLHNILGVETGGPGGRRAGESGHTVADYLKFKDLILRMLDYDPKTRIQPYYALQHSFFK
  KTADEGTNTSNSVSTSPAMEQSQSSGTTSSTSSSSGGSSGTSNSGRARSDPTHQHRHSGG
  HFTAAVQAMDCETHSPQVRQQFPAPLGWSGTEAPTQVTVETHPVQETTFHVAPQQNALHH
  HHGNSSHHHHHHHHHHHHHGQQALGNRTRPRVYNSPTNSSSTQDSMEVGHSHHSMTSLSS
  STTSSSTSSSSTGNQGNQAYQNRPVAANTLDFGQNGAMDVNLTVYSNPRQETGIAGHPTY
  QFSANTGPAHYMTEGHLTMRQGADREESPMTGVCVQQSPVASS
• Function: Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Exhibits a substrate preference for proline at position P+1 and arginine at position P-3. Plays an important role in double-strand breaks (DSBs) repair following DNA damage. Mechanistically, phosphorylates RNF169 and increases its ability to block accumulation of TP53BP1 at the DSB sites thereby promoting homologous recombination repair (HRR). Also acts as a positive regulator of transcription by acting as a CTD kinase that mediates phosphorylation of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A. May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6. Has pro-survival function and negatively regulates the apoptotic process. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits p53/TP53 activity and apoptosis. Phosphorylates SEPTIN4, SEPTIN5 and SF3B1 at 'Thr-434'.
• Tissue Specificity: Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney.
• Reactome Pathway: G0 and Early G1 (R-HSA-1538133)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
DYRK1A-related intellectual disability syndrome	DISFVO8G	Definitive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) increases the response to substance of Arsenic trioxide.	[19]

18 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 1A (DYRK1A).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[11]
R-roscovitine	DMSH108	Phase 2	R-roscovitine decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[17]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[18]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[11]
Purvalanol A	DMNQ7TM	Investigative	Purvalanol A decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[11]
SU 6656	DMF1P6W	Investigative	SU 6656 decreases the activity of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [7] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [11] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [12] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Licocoumarone induces BxPC-3 pancreatic adenocarcinoma cell death by inhibiting DYRK1A. Chem Biol Interact. 2020 Jan 25;316:108913. doi: 10.1016/j.cbi.2019.108913. Epub 2019 Dec 12.
• [19] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.