Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2B9KF)

• DTT Name: Fyn tyrosine protein kinase (FYN)
• Synonyms: Tyrosine-protein kinase Fyn; Src-like kinase; SLK; Proto-oncogene tyrosine-protein kinase Fyn; Proto-oncogene c-Fyn; Proto-oncogene Syn; Fyn p59-Fyn; Fyn Protooncogene Syn
• Gene Name: FYN
• DTT Type: Successful target; [1]
• Related Disease: Myeloproliferative neoplasm [ICD-11: 2A20]
• BioChemical Class: Kinase
• UniProt ID: FYN_HUMAN
• TTD ID: T17980
• EC Number: EC 2.7.10.2
• Sequence:
  MGCVQCKDKEATKLTEERDGSLNQSSGYRYGTDPTPQHYPSFGVTSIPNYNNFHAAGGQG
  LTVFGGVNSSSHTGTLRTRGGTGVTLFVALYDYEARTEDDLSFHKGEKFQILNSSEGDWW
  EARSLTTGETGYIPSNYVAPVDSIQAEEWYFGKLGRKDAERQLLSFGNPRGTFLIRESET
  TKGAYSLSIRDWDDMKGDHVKHYKIRKLDNGGYYITTRAQFETLQQLVQHYSERAAGLCC
  RLVVPCHKGMPRLTDLSVKTKDVWEIPRESLQLIKRLGNGQFGEVWMGTWNGNTKVAIKT
  LKPGTMSPESFLEEAQIMKKLKHDKLVQLYAVVSEEPIYIVTEYMNKGSLLDFLKDGEGR
  ALKLPNLVDMAAQVAAGMAYIERMNYIHRDLRSANILVGNGLICKIADFGLARLIEDNEY
  TARQGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLTELVTKGRVPYPGMNNREVLEQVE
  RGYRMPCPQDCPISLHELMIHCWKKDPEERPTFEYLQSFLEDYFTATEPQYQPGENL
• Function: Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance.
• KEGG Pathway:
  Sphingolipid signaling pathway (hsa04071)
  Axon guidance (hsa04360)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Platelet activation (hsa04611)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  Fc epsilon RI signaling pathway (hsa04664)
  Cholinergic synapse (hsa04725)
  Prion diseases (hsa05020)
  Pathogenic Escherichia coli infection (hsa05130)
  Measles (hsa05162)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Regulation of KIT signaling (R-HSA-1433559)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  FCGR activation (R-HSA-2029481)
  PECAM1 interactions (R-HSA-210990)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  DAP12 signaling (R-HSA-2424491)
  EPH-Ephrin signaling (R-HSA-2682334)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  Nephrin interactions (R-HSA-373753)
  NCAM signaling for neurite out-growth (R-HSA-375165)
  CD28 co-stimulation (R-HSA-389356)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  CTLA4 inhibitory signaling (R-HSA-389513)
  EPHB-mediated forward signaling (R-HSA-3928662)
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  CRMPs in Sema3A signaling (R-HSA-399956)
  DCC mediated attractive signaling (R-HSA-418885)
  Netrin mediated repulsion signals (R-HSA-418886)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Dectin-2 family (R-HSA-5621480)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Platelet Adhesion to exposed collagen (R-HSA-75892)
  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
Dasatinib	DMJV2EK	Chronic myelogenous leukaemia	2A20.0	Approved	[1], [2], [3]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
JNJ-26483327	DMSQ3AZ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Methoxy-2-[2-(2-Methoxy-Ethoxy]-Ethane	DMD7WNV	Discovery agent	N.A.	Investigative	[5]
CEP-5104	DMV43GY	Discovery agent	N.A.	Investigative	[6]
CEP-6331	DMNXBTD	Discovery agent	N.A.	Investigative	[6]
JNJ-10198409	DM9GDP5	Discovery agent	N.A.	Investigative	[7]
PMID15546730C2	DMOPUIH	Discovery agent	N.A.	Investigative	[8]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Multiple myeloma	2C82	Bone marrow	2.29E-01	-0.1	-0.51

References

• [1] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [2] In vitro and clinical investigation of the relationship between CCR5 receptor occupancy and anti-HIV activity of Aplaviroc. J Clin Pharmacol. 2008 Oct;48(10):1179-88.
• [3] Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007 Jan;12(1-2):34-42.
• [4] National Cancer Institute Drug Dictionary (drug id 596693).
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-linea... J Med Chem. 2008 Sep 25;51(18):5680-9.
• [7] (6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad ant... J Med Chem. 2005 Dec 29;48(26):8163-73.
• [8] Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6061-6.
• [9] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.