Target Information
Target General Infomation | |||||
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Target ID |
T62431
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Former ID |
TTDC00156
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Target Name |
Tyrosine-protein kinase SYK
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Gene Name |
SYK
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Synonyms |
Spleen tyrosine kinase; SYK
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Target Type |
Clinical Trial
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Allergy [ICD9: 995.3; ICD10: T78.4] | |||||
Asthma [ICD10: J45] | |||||
B-cell lymphoma [ICD9: 202.8; ICD10: C85.1] | |||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
Chronic lymphocytic leukaemia [ICD10: C91] | |||||
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.
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BioChemical Class |
Kinase
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Target Validation |
T62431
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UniProt ID | |||||
EC Number |
EC 2.7.10.2
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Sequence |
MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRK
AHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPF EDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQ IVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQL VEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPK PGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRP KEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAE ANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSM GMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYA PECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPRE MYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN |
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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 523163 | ClinicalTrials.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 525038 | ClinicalTrials.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 536998 | Developmental 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 548671 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027577) | ||||
Ref 548712 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027922) | ||||
Ref 549055 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031836) | ||||
Ref 526107 | J 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 527614 | Synthetic 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 528129 | J 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 528928 | Bioorg 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 528930 | Synthesis 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 529992 | Pharmacophore 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 530227 | A novel Syk kinase inhibitor suitable for inhalation: R-343(. Expert Opin Ther Pat. 2009 Oct;19(10):1469-72. | ||||
Ref 531860 | X-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 532191 | Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1051-5. | ||||
Ref 533142 | An 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 544430 | Advances in kinase inhibition: treating rheumatic diseases and beyond. Curr Opin Rheumatol. 2014 March; 26(2): 237-243. |
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