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target has curated data in GtoImmuPdb
Target id: 2230
Nomenclature: spleen associated tyrosine kinase
Abbreviated Name: Syk
Family: Syk family
Gene and Protein Information | ||||||
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 |
p72syk | Sykb |
Database Links | |
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 | |||||||||||||
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Enzyme Reaction | ||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 9,29 |
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Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Target used in screen: SYK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 1,10 |
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Target used in screen: Syk/SYK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||
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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]
Syk family: spleen associated tyrosine kinase. Last modified on 04/02/2022. Accessed on 11/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2230.