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spleen associated tyrosine kinase

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2230

Nomenclature: spleen associated tyrosine kinase

Abbreviated Name: Syk

Family: Syk family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 635 9q22.2 SYK spleen associated tyrosine kinase
Mouse - 629 13 27.41 cM Syk spleen tyrosine kinase
Rat - 629 17p14 Syk spleen associated tyrosine kinase
Previous and Unofficial Names Click here for help
p72syk | Sykb
Database Links Click here for help
Alphafold P43405 (Hs), P48025 (Mm), Q64725 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 1.10.930.10, 3.30.505.10
ChEMBL Target CHEMBL2599 (Hs), CHEMBL4364 (Rn)
Ensembl Gene ENSG00000165025 (Hs), ENSMUSG00000021457 (Mm), ENSRNOG00000012160 (Rn)
Entrez Gene 6850 (Hs), 20963 (Mm), 25155 (Rn)
Human Protein Atlas ENSG00000165025 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:6850 (Hs), mmu:20963 (Mm), rno:25155 (Rn)
OMIM 600085 (Hs)
Pharos P43405 (Hs)
RefSeq Nucleotide NM_001174167 (Hs), NM_001198977 (Mm), NM_012758 (Rn)
RefSeq Protein NP_001167638 (Hs), NP_001185906 (Mm), NP_036890 (Rn)
SynPHARM 80764 (in complex with entospletinib)
84009 (in complex with GSK143)
85059 (in complex with tamatinib)
81294 (in complex with tamatinib)
79688 (in complex with tamatinib)
UniProtKB P43405 (Hs), P48025 (Mm), Q64725 (Rn)
Wikipedia SYK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structural and biophysical characterization of the Syk activation switch.
PDB Id:  4FL2
Resolution:  2.19Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF SPLEEN TYROSINE KINASE (SYK) IN COMPLEX WITH A 2-(PHENOXYMETHYL)PYRIDINE INHIBITOR (GSK26462640.
PDB Id:  6HM7
Ligand:  GSK2646264
Resolution:  1.64Å
Species:  Human
References:  3
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

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
tamatinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.7 pKd 9
⤷ pKd 7.7 (Kd 1.9x10-8 M) [9]
mivavotinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pEC50 16
⤷ pEC50 8.0 (EC50 9.8x10-9 M) [16]
Description: Cellular potency
TAS05567 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 9.4 pIC50 13
⤷ pIC50 9.4 (IC50 3.7x10-10 M) [13]
P505-15 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 7
⤷ pIC50 9.0 (IC50 1x10-9 M) [7]
mivavotinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 16
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [16]
Description: Enzyme inhibition in vitro.
compound 23 [PMID: 17600705] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 2
⤷ pIC50 8.4 (IC50 4x10-9 M) [2]
GSK143 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 18
⤷ pIC50 8.1 (IC50 7.5x10-9 M) [18]
Description: Enzyme inhibition assay using recombinant human protein
entospletinib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 7.7x10-9 M) [8]
gusacitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >8.0 pIC50 27
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [27]
sovleplenib Small molecule or natural product Hs Inhibition 7.0 – 9.0 pIC50 24
⤷ pIC50 7.0 – 9.0 (IC50 1x10-7 – 1x10-9 M) [24]
lanraplenib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.9 pIC50 4
⤷ pIC50 7.9 (IC50 1.35x10-8 M) [4]
Syk inhibitor Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 15
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [15]
Description: Assayed using N-Flag tagged catalytic domain of human SYK (Ala340-Asn635)
BAY 61-3606 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 17
⤷ pIC50 7.6 (IC50 2.55x10-8 M) [17]
tamatinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.4 – 7.8 pIC50 5,19,30
⤷ pIC50 7.8 (IC50 1.7x10-8 M) [19]
Description: Measuring inhibition of the capacity of a truncated construct of Syk (aa 360-635) to phosphorylate a biotinylated peptide substrate.
pIC50 7.4 – 7.5 (IC50 4.1x10-8 – 3x10-8 M) [5,30]
cerdulatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 6
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [6]
Syk inhibitor II Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 14
⤷ pIC50 7.4 (IC50 4.1x10-8 M) [14]
GSK2646264 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.1 pIC50 3
⤷ pIC50 7.1 (IC50 7.94x10-8 M) [3]
apitolisib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pIC50 26
⤷ pIC50 6.9 (IC50 1.34x10-7 M) [26]
compound 7 [PMID: 22464456] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.4 pIC50 20
⤷ pIC50 6.4 (IC50 3.582x10-7 M) [20]
lazertinib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.0 – 6.7 pIC50 25
⤷ pIC50 6.0 – 6.7 (IC50 1x10-6 – 2.01x10-7 M) [25]
Description: In a biochemical enzyme activity assay.
Syk inhibitor III Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.6 pIC50 28
⤷ pIC50 5.6 (IC50 2.8x10-6 M) [28]
ER-27319 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 5.0 pIC50 23
⤷ pIC50 5.0 (IC50 1x10-5 M) [23]
Description: Inhibition of Syk in human mast cells by immunoprecipitation assay
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: 9,29
Key to terms and symbols Click column headers to sort
Target used in screen: SYK
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.9 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: 1,10
Key to terms and symbols Click column headers to sort
Target used in screen: Syk/SYK
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 4.7 1.0 0.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 6.0 1.0 2.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 14.6 3.0 5.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.5 16.0 3.0
Syk inhibitor II Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 15.6 6.0 0.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 15.8 90.0 80.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 16.5 38.0 28.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 16.8 2.0 3.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 21.1
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 36.1 18.0 3.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
SYK plays a key role in coupling activated immunoreceptors to downstream cellular responses such as proliferation, differentiation, and phagocytosis. Mast cell, macrophage and B-cell activation (and release of inflammatory modulators) is disrupted by inhibition of SYK-mediated immunoreceptor signalling. Selective SYK inhibitors are being sought for a number of inflammatory conditions including rheumatoid arthritis, B-cell lymphoma and asthma/rhinitis [11,22].

The first SYK inhibitor to receive FDA approval was fostamatinib (April 2018), which was authorised for the treatment of persistent/chronic adult immune thrombocytopenia (ITP) [21]. In ITP, SYK-mediated signal transduction in macrophages drives the phagocytosis and destruction of autoantibody-coated platelets.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

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. Bamborough P, Angell RM, Bhamra I, Brown D, Bull J, Christopher JA, Cooper AW, Fazal LH, Giordano I, Hind L et al.. (2007) N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics. Bioorg Med Chem Lett, 17 (15): 4363-8. [PMID:17600705]

3. Barker MD, Liddle J, Atkinson FL, Wilson DM, Dickson MC, Ramirez-Molina C, Lewis H, Davis RP, Somers DO, Neu M et al.. (2018) Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg Med Chem Lett, 28 (21): 3458-3462. [PMID:30249354]

4. Blomgren P, Currie KS, Kropf JE, Lee SH, Lo JR, Mitchell SA, Schmitt AC, Xiong J-M, Xu J, Zhao Z et al.. (2016) Substituted imidazo[1,2-a]pyrazines as Syk inhibitors. Patent number: US9290505. Assignee: Gilead Sciences, Inc.. Priority date: 23/12/2013. Publication date: 22/03/2016.

5. Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C et al.. (2006) R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther, 319 (3): 998-1008. [PMID:16946104]

6. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 351 (3): 538-48. [PMID:25253883]

7. Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, Betz A, Jia ZJ, Pandey A, Baker D et al.. (2012) Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther, 340 (2): 350-9. [PMID:22040680]

8. Currie KS, Kropf JE, Lee T, Blomgren P, Xu J, Zhao Z, Gallion S, Whitney JA, Maclin D, Lansdon EB et al.. (2014) Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem, 57 (9): 3856-73. [PMID:24779514]

9. 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]

10. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

11. Ghosh D, Tsokos GC. (2010) Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and inflammatory diseases. Autoimmunity, 43 (1): 48-55. [PMID:20001666]

12. Grädler U, Schwarz D, Dresing V, Musil D, Bomke J, Frech M, Greiner H, Jäkel S, Rysiok T, Müller-Pompalla D et al.. (2013) Structural and biophysical characterization of the Syk activation switch. J Mol Biol, 425 (2): 309-33. [PMID:23154170]

13. Hayashi H, Kaneko R, Demizu S, Akasaka D, Tayama M, Harada T, Irie H, Ogino Y, Fujino N, Sasaki E. (2018) TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models. J Pharmacol Exp Ther, 366 (1): 84-95. DOI: 10.1124/jpet.118.248153 [PMID:29728446]

14. Hisamichi H, Naito R, Toyoshima A, Kawano N, Ichikawa A, Orita A, Orita M, Hamada N, Takeuchi M, Ohta M et al.. (2005) Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. Bioorg Med Chem, 13 (16): 4936-51. [PMID:15990316]

15. Lai JY, Cox PJ, Patel R, Sadiq S, Aldous DJ, Thurairatnam S, Smith K, Wheeler D, Jagpal S, Parveen S et al.. (2003) Potent small molecule inhibitors of spleen tyrosine kinase (Syk). Bioorg Med Chem Lett, 13 (18): 3111-4. [PMID:12941345]

16. Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A et al.. (2016) Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett, 26 (24): 5947-5950. [PMID:27839918]

17. Lau KS, Zhang T, Kendall KR, Lauffenburger D, Gray NS, Haigis KM. (2012) BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. PLoS ONE, 7 (7): e41343. [PMID:22815993]

18. Liddle J, Atkinson FL, Barker MD, Carter PS, Curtis NR, Davis RP, Douault C, Dickson MC, Elwes D, Garton NS et al.. (2011) Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett, 21 (20): 6188-94. [PMID:21903390]

19. Lucas MC, Goldstein DM, Hermann JC, Kuglstatter A, Liu W, Luk KC, Padilla F, Slade M, Villaseñor AG, Wanner J et al.. (2012) Rational design of highly selective spleen tyrosine kinase inhibitors. J Med Chem, 55 (23): 10414-23. [PMID:23151054]

20. McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY et al.. (2012) X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg Med Chem Lett, 22 (9): 3296-300. [PMID:22464456]

21. Newland A, Lee EJ, McDonald V, Bussel JB. (2018) Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy, 10 (1): 9-25. [PMID:28967793]

22. Riccaboni M, Bianchi I, Petrillo P. (2010) Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov Today, 15 (13-14): 517-30. [PMID:20553955]

23. Singh R, Masuda ES, Payan DG. (2012) Discovery and development of spleen tyrosine kinase (SYK) inhibitors. J Med Chem, 55 (8): 3614-43. [PMID:22257213]

24. Su W-G, Deng W, Ji J. (2012) Substituted pyridopyrazines as novel syk inhibitors. Patent number: WO2012167733A1. Assignee: Hutchison Medipharma Limited. Priority date: 08/06/2011. Publication date: 13/12/2012.

25. Suh B-C, Salgaonkar PD, Lee J, Koh JS, Song H-J, Lee IY, Lee J, Jung DS, Kim J-H, Kim S-W. (2016) Compounds and compositions for modulating EGFR mutant kinase activities. Patent number: WO2016060443A2. Assignee: Yuhan Corporation. Priority date: 13/10/2014. Publication date: 21/04/2016.

26. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J et al.. (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem, 54 (21): 7579-87. [PMID:21981714]

27. Venkatesan A, Smith RS, Hosahalli S, Potluri V, Panigrahi SK, Basetti V, Kuntu K. (2013) Pyrimido- pyridazinone compounds and use thereof. Patent number: WO2013028818A1. Assignee: Asana Biosciences LLC. Priority date: 23/08/2011. Publication date: 28/02/2013.

28. Wang WY, Hsieh PW, Wu YC, Wu CC. (2007) Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity. Biochem Pharmacol, 74 (4): 601-11. [PMID:17601492]

29. 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]

30. Xie HZ, Li LL, Ren JX, Zou J, Yang L, Wei YQ, Yang SY. (2009) Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors. Bioorg Med Chem Lett, 19 (7): 1944-9. [PMID:19254842]

How to cite this page

Syk family: spleen associated tyrosine kinase. Last modified on 04/02/2022. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2230.