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dual specificity tyrosine phosphorylation regulated kinase 1A

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Target id: 2009

Nomenclature: dual specificity tyrosine phosphorylation regulated kinase 1A

Abbreviated Name: DYRK1A

Family: Dyrk1 subfamily

Contents:

Gene and Protein Information Click here for help
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 55.3 cM Dyrk1a dual-specificity tyrosine phosphorylation regulated kinase 1a
Rat - 763 11q11 Dyrk1a dual specificity tyrosine phosphorylation regulated kinase 1A
Previous and Unofficial Names Click here for help
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 Click here for help
Alphafold Q13627 (Hs), Q61214 (Mm), Q63470 (Rn)
BRENDA 2.7.12.1
ChEMBL Target CHEMBL2292 (Hs), CHEMBL4750 (Mm), CHEMBL5508 (Rn)
Ensembl Gene ENSG00000157540 (Hs), ENSMUSG00000022897 (Mm), ENSRNOG00000001662 (Rn)
Entrez Gene 1859 (Hs), 13548 (Mm), 25255 (Rn)
Human Protein Atlas ENSG00000157540 (Hs)
KEGG Enzyme 2.7.12.1
KEGG Gene hsa:1859 (Hs), mmu:13548 (Mm), rno:25255 (Rn)
OMIM 600855 (Hs)
Orphanet ORPHA270014 (Hs)
Pharos Q13627 (Hs)
RefSeq Nucleotide NM_001396 (Hs), NM_001113389 (Mm), NM_012791 (Rn)
RefSeq Protein NP_001387 (Hs), NP_001106860 (Mm), NP_036923 (Rn)
SynPHARM 83925 (in complex with harmine)
UniProtKB Q13627 (Hs), Q61214 (Mm), Q63470 (Rn)
Wikipedia DYRK1A (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Human DYRK1A/inhibitor complex
PDB Id:  3ANQ
Resolution:  2.6Å
Species:  Human
References:  19
Image of receptor 3D structure from RCSB PDB
Description:  DYRK1A bound to a harmine derivative
PDB Id:  6UWY
Ligand:  compound 2-2c [PMID: 32003560]
Resolution:  2.95Å
Species:  Human
References:  15
Enzyme Reaction Click here for help
EC Number: 2.7.12.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
leucettine L41 Small molecule or natural product Rn Inhibition 10.4 pIC50 6
⤷ pIC50 10.4 (IC50 4x10-11 M) [6]
compound 68 [PMID: 24900699] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.8 pIC50 21
⤷ pIC50 9.8 (IC50 1.6x10-10 M) [21]
compound 72 [WO2013026806] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.7 pIC50 16
⤷ pIC50 9.7 (IC50 2.2x10-10 M) [16]
cirtuvivint Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 8
⤷ pIC50 9.0 (IC50 1x10-9 M) [8]
Description: Determined in a non-radioactive fluorescence resonance energy transfer (FRET) assay for kinase activity.
compound 17 [PMID: 23642479] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 4
⤷ pIC50 8.4 (IC50 4x10-9 M) [4]
GNF4877 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pIC50 23
⤷ pIC50 8.2 (IC50 6x10-9 M) [23]
GNF2133 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.2 pIC50 17
⤷ pIC50 8.2 (IC50 6.2x10-9 M) [17]
compound 2-2c [PMID: 32003560] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.6 pIC50 15
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [15]
lorecivivint Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.6 pIC50 7
⤷ pIC50 7.6 (IC50 2.69x10-8 M) [7]
compound 3b [PMID: 23454515] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pIC50 3
⤷ pIC50 7.6 (IC50 2.8x10-8 M) [3]
harmine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 12
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [12]
KH-CB19 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 10
⤷ pIC50 7.3 (IC50 5.52x10-8 M) [10]
ML315 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 4
⤷ pIC50 6.6 (IC50 2.82x10-7 M) [4]
epigallocatechin-3-gallate Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.5 pIC50 11
⤷ pIC50 6.5 (IC50 3.3x10-7 M) [11]
(S)-CR8 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.1 pIC50 13
⤷ pIC50 6.1 (IC50 9x10-7 M) [13]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen Click here for help
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: 5,25
Key to terms and symbols Click column headers to sort
Target used in screen: DYRK1A
Ligand Sp. Type Action Value Parameter
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
R547 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
AT-7519 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
enzastaurin Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 Click here for help
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.6
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 5.1
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 8.7
K-252a Small molecule or natural product Hs Inhibitor Inhibition 11.7
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.3
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.4
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 20.7
PI 3-Kg inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 21.8
Cdc2-like kinase inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 28.9
PKCbeta inhibitor Small molecule or natural product Hs Inhibitor Inhibition 30.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
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. This kinase can directly and indirectly regulate phosphorylation of tau on numerous residues [2,22], and its inhibition is predicted to reduce hyperphosphorylation of tau and its aggregation in neurodegenerative tauopathies. The selective DYRK1A inhibitor SM07883 (Samumed) reduces phospho-tau and tau pathology in preclinical models [18].
DYRK1A acts as a regulator of regenerative pathways that are associated with human insulin-producing pancreatic β-cells. DYRK1A inhibitors are being examined for their potential to promote proliferation of functional β-cells as a novel strategy to treat type 1 diabetes [9,14-15,17,20,23-24].

References

Show »

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. Azorsa DO, Robeson RH, Frost D, Meec hoovet B, Brautigam GR, Dickey C, Beaudry C, Basu GD, Holz DR, Hernandez JA et al.. (2010) High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation. BMC Genomics, 11: 25. [PMID:20067632]

3. 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]

4. 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]

5. 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]

6. 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]

7. Deshmukh V, Hu H, Barroga C, Bossard C, Kc S, Dellamary L, Stewart J, Chiu K, Ibanez M, Pedraza M et al.. (2018) A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthr Cartil, 26 (1): 18-27. [PMID:28888902]

8. Deshmukh V, O'Green AL, Bossard C, Barroga CF, Hood J. (2020) Methods of treating cartilage disorders through inhibition of clk and dyrk. Patent number: WO2020150552A2. Assignee: Samumed, Llc. Priority date: 17/01/2020. Publication date: 23/07/2020.

9. Dirice E, Walpita D, Vetere A, Meier BC, Kahraman S, Hu J, Dančík V, Burns SM, Gilbert TJ, Olson DE et al.. (2016) Inhibition of DYRK1A Stimulates Human β-Cell Proliferation. Diabetes, 65 (6): 1660-71. [PMID:26953159]

10. 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]

11. Feki A, Hibaoui Y. (2018) DYRK1A Protein, A Promising Therapeutic Target to Improve Cognitive Deficits in Down Syndrome. Brain Sci, 8 (10). [PMID:30332747]

12. 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]

13. Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS. (2018) Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. J Med Chem, 61 (22): 9791-9810. [PMID:29985601]

14. Kumar K, Suebsuwong C, Wang P, Garcia-Ocana A, Stewart AF, DeVita RJ. (2021) DYRK1A Inhibitors as Potential Therapeutics for β-Cell Regeneration for Diabetes. J Med Chem, 64 (6): 2901-2922. [PMID:33682417]

15. Kumar K, Wang P, Wilson J, Zlatanic V, Berrouet C, Khamrui S, Secor C, Swartz EA, Lazarus M, Sanchez R et al.. (2020) Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor. J Med Chem, 63 (6): 2986-3003. [PMID:32003560]

16. 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.

17. Liu YA, Jin Q, Zou Y, Ding Q, Yan S, Wang Z, Hao X, Nguyen B, Zhang X, Pan J et al.. (2020) Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133. J Med Chem, 63 (6): 2958-2973. [PMID:32077280]

18. Melchior B, Mittapalli GK, Lai C, Duong-Polk K, Stewart J, Güner B, Hofilena B, Tjitro A, Anderson SD, Herman DS et al.. (2019) Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease. Aging Cell, 18 (5): e13000. [PMID:31267651]

19. 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]

20. Rachdi L, Kariyawasam D, Aïello V, Herault Y, Janel N, Delabar JM, Polak M, Scharfmann R. (2014) Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance. Cell Cycle, 13 (14): 2221-9. [PMID:24870561]

21. 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]

22. Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH et al.. (2007) DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease. J Biol Chem, 282 (48): 34850-7. [PMID:17906291]

23. Shen W, Taylor B, Jin Q, Nguyen-Tran V, Meeusen S, Zhang YQ, Kamireddy A, Swafford A, Powers AF, Walker J et al.. (2015) Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat Commun, 6: 8372. [PMID:26496802]

24. Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, Kumar A, Sanchez R, Scott DK, Garcia-Ocaña A et al.. (2015) A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med, 21 (4): 383-8. [PMID:25751815]

25. 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 19/04/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2009.