Lck kinase

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

In addition to the Lck kinase, other tyrosine kinases are activated on ligand binding to the IL-2 receptor. These are Fyn kinase and the Janus kinases Jakl and Jak3. 

Pyrazolo[4,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized as selective calcitonin inducers <02JMC2342>. A series of para-substituted 3-arylpyrazolo[3,4-d]pyrimidines have been synthesized and evaluated as inhibitors of lck kinase <02BMCL1687). The synthesis of 3-aryl-pyrazolo[4,3- f]pyrimidines as potential corticotropin-releasing factor (CRF-1) antagonists has been described <02BMCL2133>. Cyclization of 4-chloro-5-heteroimine-l,2,3-thiadiazoles furnished pyrazolo[3,4-d]pyrimidines, triazolo[4,5-d]pyrimidines and purines <02BMC449>. 

Yamaguchi, H., Hendrickson, W. Structural basis for activation of human kinase Lck upon tyrosine phosphorylation. Nature 384 484-489, 1996. 

Imatinib (Gleevec) TKI Bcr-Abl, c-Kit, PDGFR, Lck Inhibition of kinase activity - ATP-competitive, binding to an inactive conformation CML ALL GIST DFSP MDS/MPD ASM HES/CEL... 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

The synthesis of some novel acyclonucleosides involving pyrrolo[2,3-c]pyridazine and a 4-hydroxybutyl side chain has been reported <00H(53)5>. New pyrrolo[2,3-pyrimidines containing an extended 5-substituent, as potent and selective inhibitors of lck (an src-family tyrosine kinase), have been synthesized and tested <00BMCL2171>. 

The Src kinase Hck has been crystallized in its inactive form with the inhibitor PP1 complexed with it [26]. Similarly, Lck in its active form has been crystallized with the inhibitor PP2 [27]. 

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. 

SU-6656 (12) [113-115] is a potent inhibitor of Src kinase (as well as Lck, Fyn, and Yes kinases) and is an effective inhibitor of PDGF-stimulated DNA synthesis and Myc induction in a fibroblast cell line. SU-6656 has also been a useful tool for investigating the role of Src and Ras-ERK signal transduction in Src-transformed cells with respect to Racl, as well as implicating Vav2 and Tiaml as downstream effectors of Src to modulate Racl-dependent pathways. In endothelial cells, SU-6656 is effective in increasing radiation-induced apoptosis and vascular endothelium destruction, and in vivo studies have... 

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