Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUMHT8)

• DTT Name: Tyrosine-protein kinase ZAP-70 (ZAP-70)
• Synonyms: Syk-related tyrosine kinase; SRK; 70 kDa zeta-chain associated protein
• Gene Name: ZAP70
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: ZAP70_HUMAN
• TTD ID: T64553
• EC Number: EC 2.7.10.2
• Sequence:
  MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFP
  IERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRD
  AMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSG
  AQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLK
  LKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARIT
  SPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMR
  KKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGG
  PLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDF
  GLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPY
  KKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSL
  ASKVEGPPGSTQKAEAACA
• Function: Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  NF-kappa B signaling pathway (hsa04064)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Generation of second messenger molecules (R-HSA-202433)
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)

Molecular Interaction Atlas (MIA) of This DTT

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
US8546370, 102	DMQRO6G	N. A.	N. A.	Patented	[2]
US8546370, 11	DM2K6YU	N. A.	N. A.	Patented	[2]
US8546370, 17	DMGIJZA	N. A.	N. A.	Patented	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
aloisine	DM7HGX8	Discovery agent	N.A.	Investigative	[3]
K00592a	DM1RP5Q	Discovery agent	N.A.	Investigative	[1]

References

• [1] 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.
• [2] Compounds and compositions as kinase inhibitors. US8546370.
• [3] Identification of binding specificity-determining features in protein families. J Med Chem. 2012 Mar 8;55(5):1926-39.