Zap-70 kinase

The ALIS-based off-rate measurement method was applied to a proprietary series of Zap-70 Kinase inhibitors. First, an ACE50 experiment was conducted to demonstrate that the compounds bind the same site as the quench reagent staurospor-ine. As shown in Fig. 3.15, sigmoidal plots indicate that, with the exception of one compound, the ACE50 values were all very similar to one-another. Linear ratio plots of the same ACE50 data confirm that the compounds all bind isosteri-cally with respect to the quench reagent, a necessary prerequisite for effective competition. 

Fig. 3.15 (A) An ALIS competition experiment with a proprietary series of Zap-70 kinase inhibitors at 0.5 pM per component plus receptor at 5 pM concentration yields similar ACE50 values, indicating that all but one of the compounds have similar K s. (B) Linear ratio plots of the ACE50 data in (A) confirm that the compounds all bind isosterically with respect to staurosporine.

Table 3.2 IC50 values and protein-ligand dissociation half-lives for a proprietary series of Zap-70 Kinase inhibitors.

E. Arpaia, M. Shahar, H. Dadi, A. Cohen, and C. M. Roifinan. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. CeU, 76 (5), 947-958, 1994. 

ZAP-70 expression An intracellular tyrosine kinase found in B cells in chronic lymphocytic leukemia. 

Ottoson NC, Pribila JT, Chan AS, Shimizu Y. Cutting edge T cell migration regulated by CXCR4 chemokine receptor signaling to ZAP-70 tyrosine kinase. J Immunol 2001 167(4) 1857-1861. 

Oxadiazole amine 174 serves as an excellent template for the introduction of a wide variety of 5-amido side chains onto the 1,2,4-oxadiazole nucleus (Equation 26), and several such products 175 are potent inhibitors of the tyrosine kinase ZAP-70 <1999BML3009>. Amide or pseudopeptide side chains can also be introduced by the... 

Faith A, Akdis CA, Akdis M, Simon H-U, Blaser K Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. J Immunol 1997 159 53-60. 

PPl (8) and its pyrazolopyrimidine analog PP2 (9) [99-108] were first described as potent inhibitors of SFKs with marked selectivity versus ZAP-70, JAK2, EGF-R, and PKA kinases. PPl provided an early key inhibitor of Src kinase to enable determination of its roles in VEGF-mediated angiogenesis and vascular permeability, Src-driven human breast cancer cell lines with respect to both heregulin-dependent or independent growth, and Src-related,... 

Shape constrained natural compounds (tocopherol homologues, vitamin E)" protein kinase ZAP-70 tryptic fragment containing amino acids 485 96 cartenoids from a spinach sample isoflavines in Radix astragali ... 

Fig. 8.14 Domain structure of cytoplasmic tyrosine kinases. Linear representation of the domain structure of selected cytoplasmic tyrosine kinases. Details of the cytoplasmic tyrosine kinases Src 8.3.2 Jak, Tyk 11.1.5 Zap-70 11.2.2 Fak 11.3 JH Jak homology region. According to Taniguchi, (1995).

Signaling by an activated T-cell receptor is quite complex. The ITAMs are sites of tyrosine phosphorylation by kinases of the Src family.335 336 Another tyrosine kinase, Zap-70 (Fig. 31-15), associates with the C-terminal tails of the disulfide-linked dimer of subunits C- It recognizes the phosphotyrosines groups via its SH2 domains (see Fig. 7-30). Zap-70 appears to act... 

Protein kinase substrate/inhibitor (Csk, 3 bp2, Fps Fes, Grb-2, Hep, She, Syk, Vav, Zap-70) Fpitope mapping for monoclonal antibodies SH2 domain-binding peptides and kinase domains of protein tyrosine kinases... 

Figure 33.30. T-Cell Activatiou. The interaction between the T-cell receptor and a class I MHC-peptide complex results in the binding of CDS to the MHC protein, the recruitment of the protein tyrosine kinase Lck, and the phosphorylation of tyrosine residues in the ITAM sequences of the CD3 chains. After phosphorylation, the ITAM regions serve as docking sites for the protein kinase ZAP-70, which phosphorylates protein targets to transmit the signal.

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