Target Information
Target General Information | Top | |||||
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Target ID |
T62431
(Former ID: TTDC00156)
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Target Name |
Tyrosine-protein kinase SYK (SYK)
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Synonyms |
p72-Syk; Spleen tyrosine kinase
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Gene Name |
SYK
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Thrombocytopenia [ICD-11: 3B64] | |||||
Function |
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. Required for the stimulation of neutrophil phagocytosis by IL15. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils. 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 is for 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 that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response. Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR).
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BioChemical Class |
Kinase
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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 Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Fostamatinib | Drug Info | Approved | Immune thrombocytopenic purpura | [2] | |
Clinical Trial Drug(s) | [+] 12 Clinical Trial Drugs | + | ||||
1 | Fostamatinib disodium | Drug Info | Phase 3 | Thrombocytopenia | [3] | |
2 | Cerdulatinib | Drug Info | Phase 2 | B-cell lymphoma | [4] | |
3 | GS-9876 | Drug Info | Phase 2 | Cutaneous lupus erythematosus | [5] | |
4 | GS-9973 | Drug Info | Phase 2 | B-cell lymphoma | [6], [7] | |
5 | TAK-659 | Drug Info | Phase 2 | Diffuse large B-cell lymphoma | [4] | |
6 | HM43239 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [8] | |
7 | GSK2646264 | Drug Info | Phase 1 | Cutaneous lupus erythematosus | [5] | |
8 | HMPL-523 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [9] | |
9 | PRT-062607 | Drug Info | Phase 1 | Chronic lymphocytic leukaemia | [10], [11] | |
10 | PRT6207 | Drug Info | Phase 1 | Solid tumour/cancer | [12] | |
11 | SKI-O-703 | Drug Info | Phase 1 | Rheumatoid arthritis | [13] | |
12 | tamatinib | Drug Info | Clinical trial | Solid tumour/cancer | [14] | |
Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
1 | R-343 | Drug Info | Discontinued in Phase 2 | Asthma | [15] | |
2 | PF-3526299 | Drug Info | Discontinued in Phase 1 | Asthma | [16] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 4 Modulator drugs | + | ||||
1 | Fostamatinib | Drug Info | [17] | |||
2 | Cerdulatinib | Drug Info | [18] | |||
3 | GS-9973 | Drug Info | [19] | |||
4 | PRT6207 | Drug Info | [23] | |||
Inhibitor | [+] 25 Inhibitor drugs | + | ||||
1 | Fostamatinib disodium | Drug Info | [3] | |||
2 | GS-9876 | Drug Info | [5], [13] | |||
3 | TAK-659 | Drug Info | [20] | |||
4 | HM43239 | Drug Info | [21] | |||
5 | GSK2646264 | Drug Info | [5] | |||
6 | HMPL-523 | Drug Info | [22] | |||
7 | PRT-062607 | Drug Info | [23] | |||
8 | SKI-O-703 | Drug Info | [13] | |||
9 | tamatinib | Drug Info | [24] | |||
10 | Pyrimidopyridazinone derivative 1 | Drug Info | [25] | |||
11 | Pyrimidopyridazinone derivative 2 | Drug Info | [25] | |||
12 | Pyrrolo-pyrazine derivative 3 | Drug Info | [26] | |||
13 | Pyrrolo-pyrazine derivative 4 | Drug Info | [26] | |||
14 | R-343 | Drug Info | [27] | |||
15 | PF-3526299 | Drug Info | [28] | |||
16 | CG-103065 | Drug Info | [17] | |||
17 | DNX-2000 | Drug Info | [17] | |||
18 | ELLAGIC ACID | Drug Info | [29] | |||
19 | K00592a | Drug Info | [30] | |||
20 | N-Benzyl-4-(2,5-dihydroxy-benzylamino)-benzamide | Drug Info | [31] | |||
21 | PMID17600705C23 | Drug Info | [32] | |||
22 | PMID23312943C21 | Drug Info | [33] | |||
23 | PRT-060318 | Drug Info | [17] | |||
24 | SBB007833 | Drug Info | [34] | |||
25 | VRT-750018 | Drug Info | [17] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 6 | URL: 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 7 | Clinical pipeline report, company report or official report of Gilead. | |||||
REF 8 | ClinicalTrials.gov (NCT03850574) Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM43239 in Patients With Relapsed or Refractory Acute Myeloid Leukemia. U.S. National Institutes of Health. | |||||
REF 9 | ClinicalTrials.gov (NCT03779113) An Open-label, Dose Escalation Trial to Evaluate the Safety and Pharmacokinetics of HMPL-523 in Patients With Lymphoma. U.S. National Institutes of Health. | |||||
REF 10 | URL: 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 11 | 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 12 | More 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 13 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 14 | 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 15 | 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 16 | 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 17 | URL: 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 18 | Company report (Portola Pharmaceuticals) | |||||
REF 19 | 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 20 | J Clin Oncol 32:5s, 2014 (suppl; abstr 8580). | |||||
REF 21 | Clinical pipeline report, company report or official report of Hanmi Pharmaceutical. | |||||
REF 22 | Clinical pipeline report, company report or official report of Hutchison MediPharma. | |||||
REF 23 | Advances in kinase inhibition: treating rheumatic diseases and beyond. Curr Opin Rheumatol. 2014 March; 26(2): 237-243. | |||||
REF 24 | 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 25 | Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143. | |||||
REF 26 | Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2.Expert Opin Ther Pat. 2017 Feb;27(2):145-161. | |||||
REF 27 | A novel Syk kinase inhibitor suitable for inhalation: R-343(. Expert Opin Ther Pat. 2009 Oct;19(10):1469-72. | |||||
REF 28 | Pipeline report of RIGEL Pharmaceuticals. | |||||
REF 29 | Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. J Med Chem. 2006 Apr 20;49(8):2363-6. | |||||
REF 30 | 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 31 | Design, synthesis, and biological evaluation of a series of lavendustin A analogues that inhibit EGFR and Syk tyrosine kinases, as well as tubulin ... J Med Chem. 2001 Feb 1;44(3):441-52. | |||||
REF 32 | N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. | |||||
REF 33 | 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 34 | 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. |
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