Target General Infomation
Target ID
T62431
Former ID
TTDC00156
Target Name
Tyrosine-protein kinase SYK
Gene Name
SYK
Synonyms
Spleen tyrosine kinase; SYK
Target Type
Clinical Trial
Disease Allergy [ICD9: 995.3; ICD10: T78.4]
Asthma [ICD10: J45]
Autoimmune diabetes [ICD10: E08-E13]
B-cell lymphoma [ICD9: 202.8; ICD10: C85.1]
Chronic lymphocytic leukaemia [ICD10: C91]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Non-hodgkin's lymphoma [ICD10: C85]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Thrombosis [ICD9: 437.6, 453, 671.5, 671.9; ICD10: I80-I82]
Function
Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T- cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It isfor instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B thatis required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.
BioChemical Class
Kinase
Target Validation
T62431
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRK
AHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPF
EDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQ
IVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQL
VEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPK
PGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRP
KEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAE
ANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSM
GMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYA
PECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPRE
MYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN
Drugs and Mode of Action
Drug(s) Fostamatinib Drug Info Phase 3 Rheumatoid arthritis [523163], [542747]
GS-9973 Drug Info Phase 2 B-cell lymphoma [542814], [550820]
Cerdulatinib Drug Info Phase 1/2 Non-hodgkin's lymphoma [551978]
TAK-659 Drug Info Phase 1/2 Hematological malignancies [525038]
PRT-062607 Drug Info Phase 1 Chronic lymphocytic leukaemia [542953], [549055]
PRT6207 Drug Info Phase 1 Cancer [551514]
tamatinib Drug Info Clinical trial Solid tumours [536998]
R-343 Drug Info Discontinued in Phase 2 Asthma [548671]
PF-3526299 Drug Info Discontinued in Phase 1 Asthma [548712]
Modulator Cerdulatinib Drug Info
Fostamatinib Drug Info [543580]
GS-9973 Drug Info [533142]
PRT6207 Drug Info [544430]
Inhibitor CG-103065 Drug Info [543580]
compound 21 Drug Info [532191]
compound 23 Drug Info [528928]
compound 7 Drug Info [531860]
DNX-2000 Drug Info [543580]
ELLAGIC ACID Drug Info [528129]
K00592a Drug Info [527614]
N-Benzyl-4-(2,5-dihydroxy-benzylamino)-benzamide Drug Info [526107]
PF-3526299 Drug Info [551593]
PRT-060318 Drug Info [543580]
PRT-062607 Drug Info [544430]
R-343 Drug Info [530227]
SBB007833 Drug Info [528930]
Sti-571 Drug Info [551391]
Syk kinase inhibitors Drug Info [543580]
TAK-659 Drug Info [549697]
tamatinib Drug Info [529992]
VRT-750018 Drug Info [543580]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
PI3K-Akt signaling pathway
Osteoclast differentiation
Platelet activation
Natural killer cell mediated cytotoxicity
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Tuberculosis
Epstein-Barr virus infection
Viral carcinogenesis
PANTHER Pathway B cell activation
Pathway Interaction Database Fc-epsilon receptor I signaling in mast cells
BCR signaling pathway
GMCSF-mediated signaling events
Atypical NF-kappaB pathway
Osteopontin-mediated events
FAS (CD95) signaling pathway
Thromboxane A2 receptor signaling
IL2-mediated signaling events
Class I PI3K signaling events
Alpha-synuclein signaling
PathWhiz Pathway Fc Epsilon Receptor I Signaling in Mast Cells
Reactome GPVI-mediated activation cascade
FCGR activation
Regulation of actin dynamics for phagocytic cup formation
Role of phospholipids in phagocytosis
DAP12 signaling
Fc epsilon receptor (FCERI) signaling
Role of LAT2/NTAL/LAB on calcium mobilization
FCERI mediated MAPK activation
FCERI mediated Ca+2 mobilization
Integrin alphaIIb beta3 signaling
Interleukin-2 signaling
CLEC7A (Dectin-1) signaling
Dectin-2 family
Regulation of signaling by CBL
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
WikiPathways IL-2 Signaling Pathway
IL-3 Signaling Pathway
Fc epsilon receptor (FCERI) signaling
Signaling by the B Cell Receptor (BCR)
Interleukin-2 signaling
Fcgamma receptor (FCGR) dependent phagocytosis
DAP12 interactions
B Cell Receptor Signaling Pathway
RANKL/RANK Signaling Pathway
Integrin alphaIIb beta3 signaling
GPVI-mediated activation cascade
Regulation of toll-like receptor signaling pathway
IL-5 Signaling Pathway
References
Ref 523163ClinicalTrials.gov (NCT01197521) Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Not Responding.. U.S. National Institutes of Health.
Ref 525038ClinicalTrials.gov (NCT02323113) Safety, Tolerability, and Efficacy of TAK-659 in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (AML). U.S. National Institutes of Health.
Ref 536998Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res A Clin Mol Teratol. 2009 Feb;85(2):130-6.
Ref 542747(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7796).
Ref 542814(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7889).
Ref 542953(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8070).
Ref 548671Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027577)
Ref 548712Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027922)
Ref 549055Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031836)
Ref 550820Clinical pipeline report, company report or official report of Gilead.
Ref 551514More Than 900 Medicines and Vaccines in Clinical Testing Offer New Hope in the Fight Against Cancer. Pharmaceutical Research and Manufacturers of America report. 2012.
Ref 551978Clinical pipeline report, company report or official report of Portola.
Ref 526107J Med Chem. 2001 Feb 1;44(3):441-52.Design, synthesis, and biological evaluation of a series of lavendustin A analogues that inhibit EGFR and Syk tyrosine kinases, as well as tubulin polymerization.
Ref 527614Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. Bioorg Med Chem. 2005 Aug 15;13(16):4936-51.
Ref 528129J Med Chem. 2006 Apr 20;49(8):2363-6.Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Ref 528928Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. Epub 2007 Apr 13.N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.
Ref 528930Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity. Biochem Pharmacol. 2007 Aug 15;74(4):601-11. Epub 2007 Jun 3.
Ref 529992Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors. Bioorg Med Chem Lett. 2009 Apr 1;19(7):1944-9.
Ref 530227A novel Syk kinase inhibitor suitable for inhalation: R-343(. Expert Opin Ther Pat. 2009 Oct;19(10):1469-72.
Ref 531860X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg Med Chem Lett. 2012 May 1;22(9):3296-300.
Ref 532191Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1051-5.
Ref 533142An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015 Apr 9;125(15):2336-43.
Ref 543580(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2230).
Ref 544430Advances in kinase inhibition: treating rheumatic diseases and beyond. Curr Opin Rheumatol. 2014 March; 26(2): 237-243.
Ref 549697J Clin Oncol 32:5s, 2014 (suppl; abstr 8580).
Ref 551391DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
Ref 551593Pipeline report of RIGEL Pharmaceuticals.

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