Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTOU65C)

• DTT Name: Tyrosine-protein kinase SYK (SYK)
• Synonyms: p72-Syk; Spleen tyrosine kinase
• Gene Name: SYK
• DTT Type: Successful target; [1]
• Related Disease: Thrombocytopenia [ICD-11: 3B64]
• BioChemical Class: Kinase
• UniProt ID: KSYK_HUMAN
• TTD ID: T62431
• EC Number: EC 2.7.10.2
• Sequence:
  MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRK
  AHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPF
  EDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQ
  IVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQL
  VEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPK
  PGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRP
  KEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAE
  ANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSM
  GMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYA
  PECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPRE
  MYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN
• 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).
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  PI3K-Akt signaling pathway (hsa04151)
  Osteoclast differentiation (hsa04380)
  Platelet activation (hsa04611)
  Natural killer cell mediated cytotoxicity (hsa04650)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Tuberculosis (hsa05152)
  Epstein-Barr virus infection (hsa05169)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  FCGR activation (R-HSA-2029481)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  DAP12 signaling (R-HSA-2424491)
  Fc epsilon receptor (FCERI) signaling (R-HSA-2454202)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  FCERI mediated MAPK activation (R-HSA-2871796)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Integrin alphaIIb beta3 signaling (R-HSA-354192)
  Interleukin-2 signaling (R-HSA-451927)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Dectin-2 family (R-HSA-5621480)
  Regulation of signaling by CBL (R-HSA-912631)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fostamatinib	DM6AUHV	Immune thrombocytopenic purpura	3B64.13	Approved	[2]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fostamatinib disodium	DM3274D	Thrombocytopenia	3B64	Phase 3	[3]
Cerdulatinib	DMSCR2H	B-cell lymphoma	2A86	Phase 2	[4]
GS-9876	DM9Q2B6	Cutaneous lupus erythematosus	EB5Z	Phase 2	[5], [6]
GS-9973	DMKWCTR	Acute myeloid leukaemia	2A60	Phase 2	[7]
TAK-659	DMJH3U0	Diffuse large B-cell lymphoma	2A81	Phase 2	[8]
HM43239	DMV1SDA	Acute myeloid leukaemia	2A60	Phase 1/2	[9]
GSK2646264	DMQOM5V	Cutaneous lupus erythematosus	EB5Z	Phase 1	[6]
HMPL-523	DMXZ1A8	Non-hodgkin lymphoma	2B33.5	Phase 1	[10]
PRT-062607	DMBL7CW	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[11]
PRT6207	DMP5CLY	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
SKI-O-703	DMTSKXR	Rheumatoid arthritis	FA20	Phase 1	[5]
tamatinib	DMGANIC	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[12]

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pyrimidopyridazinone derivative 1	DM32N7D	N. A.	N. A.	Patented	[13]
Pyrimidopyridazinone derivative 2	DMD1RT0	N. A.	N. A.	Patented	[13]
Pyrrolo-pyrazine derivative 3	DMLM6DT	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrazine derivative 4	DMD1S92	N. A.	N. A.	Patented	[14]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
R-343	DMEJNM1	Asthma	CA23	Discontinued in Phase 2	[15]
PF-3526299	DMMU1W3	Asthma	CA23	Discontinued in Phase 1	[16]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CG-103065	DMGW9QL	Solid tumour/cancer	2A00-2F9Z	Investigative	[2]
DNX-2000	DMC5RL7	Autoimmune diabetes	5A10	Investigative	[2]
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[17]
K00592a	DM1RP5Q	Discovery agent	N.A.	Investigative	[18]
N-Benzyl-4-(2,5-dihydroxy-benzylamino)-benzamide	DMUD85N	Discovery agent	N.A.	Investigative	[19]
PMID17600705C23	DMJFOGW	Discovery agent	N.A.	Investigative	[20]
PMID23312943C21	DMOJ8QR	Discovery agent	N.A.	Investigative	[21]
PRT-060318	DMQPEA7	Thrombosis	DB61-GB90	Investigative	[2]
SBB007833	DMU8KGB	Discovery agent	N.A.	Investigative	[22]
VRT-750018	DMFT49S	Allergy	4A80-4A85	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	5.20E-02	-0.57	-0.67
Asthma	CA23	Nasal and bronchial airway	3.05E-05	0.29	0.43

References

• [1] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [2] 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).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Company report (Portola Pharmaceuticals)
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] 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.
• [8] J Clin Oncol 32:5s, 2014 (suppl; abstr 8580).
• [9] Clinical pipeline report, company report or official report of Hanmi Pharmaceutical.
• [10] Clinical pipeline report, company report or official report of Hutchison MediPharma.
• [11] Advances in kinase inhibition: treating rheumatic diseases and beyond. Curr Opin Rheumatol. 2014 March; 26(2): 237-243.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] A novel Syk kinase inhibitor suitable for inhalation: R-343(. Expert Opin Ther Pat. 2009 Oct;19(10):1469-72.
• [16] Pipeline report of RIGEL Pharmaceuticals.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1051-5.
• [22] 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.