dual specificity tyrosine phosphorylation regulated kinase 1A | Dyrk1 subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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dual specificity tyrosine phosphorylation regulated kinase 1A

Target not currently curated in GtoImmuPdb

Target id: 2009

Nomenclature: dual specificity tyrosine phosphorylation regulated kinase 1A

Abbreviated Name: DYRK1A

Family: Dyrk1 subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 763 21q22.13 DYRK1A dual specificity tyrosine phosphorylation regulated kinase 1A
Mouse - 763 16 C4 Dyrk1a dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a
Rat - 763 11 q11 Dyrk1a dual specificity tyrosine phosphorylation regulated kinase 1A
Previous and Unofficial Names
Dual Specificity Yak1-related kinase | MNBH | MP86 | PSK47 | RP86 | dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A | dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Human DYRK1A/inhibitor complex
PDB Id:  3ANQ
Resolution:  2.6Å
Species:  Human
References:  9
Enzyme Reaction
EC Number: 2.7.12.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
leucettine L41 Rn Inhibition 10.4 pIC50 5
pIC50 10.4 (IC50 4x10-11 M) [5]
compound 68 [PMID: 24900699] Hs Inhibition 9.8 pIC50 10
pIC50 9.8 (IC50 1.6x10-10 M) [10]
compound 72 [WO2013026806] Hs Inhibition 9.7 pIC50 8
pIC50 9.7 (IC50 2.2x10-10 M) [8]
compound 17 [PMID: 23642479] Hs Inhibition 8.4 pIC50 3
pIC50 8.4 (IC50 4x10-9 M) [3]
compound 3b [PMID: 23454515] Hs Inhibition 7.6 pIC50 2
pIC50 7.6 (IC50 2.8x10-8 M) [2]
harmine Hs Inhibition 7.5 pIC50 7
pIC50 7.5 (IC50 3.3x10-8 M) [7]
KH-CB19 Hs Inhibition 7.3 pIC50 6
pIC50 7.3 (IC50 5.52x10-8 M) [6]
ML315 Hs Inhibition 6.6 pIC50 3
pIC50 6.6 (IC50 2.82x10-7 M) [3]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,11

Key to terms and symbols Click column headers to sort
Target used in screen: DYRK1A
Ligand Sp. Type Action Affinity Parameter
A-674563 Hs Inhibitor Inhibition 8.7 pKd
staurosporine Hs Inhibitor Inhibition 8.4 pKd
lestaurtinib Hs Inhibitor Inhibition 7.7 pKd
R547 Hs Inhibitor Inhibition 7.6 pKd
alvocidib Hs Inhibitor Inhibition 7.1 pKd
midostaurin Hs Inhibitor Inhibition 7.0 pKd
AT-7519 Hs Inhibitor Inhibition 6.9 pKd
enzastaurin Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Hs Inhibitor Inhibition 6.7 pKd
sunitinib Hs Inhibitor Inhibition 6.7 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: ...1

Key to terms and symbols Click column headers to sort
Target used in screen: nd/DYRK1(DYRK1A)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 4.6
JAK3 inhibitor VI Hs Inhibitor Inhibition 5.1
SB 218078 Hs Inhibitor Inhibition 8.7
K-252a Hs Inhibitor Inhibition 11.7
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 15.3
PKR inhibitor Hs Inhibitor Inhibition 15.4
dorsomorphin Hs Inhibitor Inhibition 20.7
PI 3-Kg inhibitor Hs Inhibitor Inhibition 21.8
Cdc2-like kinase inhibitor Hs Inhibitor Inhibition 28.9
PKCbeta inhibitor Hs Inhibitor Inhibition 30.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Mental retardation, autosomal dominant 7; MRD7
Synonyms: Autosomal dominant non-syndromic intellectual disability [Orphanet: ORPHA178469] [Disease Ontology: DOID:0060307]
Disease Ontology: DOID:0060307
OMIM: 614104
Orphanet: ORPHA178469
General Comments
Dyrk1A is involved in neuronal development and neurite formation and overexpression may be implicated in the Down syndrome phenotype. Aberrant Dyrk1A expression has also been implicated in neurodegeneration in both Alzheimer's and Pick disease.

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Burgy G, Tahtouh T, Durieu E, Foll-Josselin B, Limanton E, Meijer L, Carreaux F, Bazureau JP. (2013) Chemical synthesis and biological validation of immobilized protein kinase inhibitory Leucettines. Eur J Med Chem, 62: 728-37. [PMID:23454515]

3. Coombs TC, Tanega C, Shen M, Wang JL, Auld DS, Gerritz SW, Schoenen FJ, Thomas CJ, Aubé J. (2013) Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315. Bioorg. Med. Chem. Lett., 23 (12): 3654-61. [PMID:23642479]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

5. Debdab M, Carreaux F, Renault S, Soundararajan M, Fedorov O, Filippakopoulos P, Lozach O, Babault L, Tahtouh T, Baratte B et al.. (2011) Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J. Med. Chem., 54 (12): 4172-86. [PMID:21615147]

6. Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J et al.. (2011) Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem. Biol., 18 (1): 67-76. [PMID:21276940]

7. Göckler N, Jofre G, Papadopoulos C, Soppa U, Tejedor FJ, Becker W. (2009) Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. FEBS J., 276 (21): 6324-37. [PMID:19796173]

8. Leblond B, Casagrande A-S, Desire L, Foucourt A, Besson T. (2013) Dyrk1 inhibitors and uses thereof. Patent number: WO2013026806. Assignee: Exonhit Sa. Priority date: 19/08/2011. Publication date: 28/02/2013.

9. Ogawa Y, Nonaka Y, Goto T, Ohnishi E, Hiramatsu T, Kii I, Yoshida M, Ikura T, Onogi H, Shibuya H et al.. (2010) Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat Commun, 1: 86. [PMID:20981014]

10. Rosse G. (2013) Tricyclic Pyrimidines As Inhibitors of DYRK1A/DYRK1B As Potential Treatment for Down's Syndrome or Alzheimer's Disease. ACS Med Chem Lett, 4 (6): 502-3. [PMID:24900699]

11. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Dyrk1 subfamily: dual specificity tyrosine phosphorylation regulated kinase 1A. Last modified on 03/11/2016. Accessed on 27/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2009.