Kinase target validation

This was the first time that a drug-insensitive protein kinase was used for the purpose of drug target validation. Eyers et al. also discussed the general applicability to the study of other protein kinases [50], as is described in the next section. 

The protein kinases in a proteome of an organism. See Manning, G., Whyle, D.B., Martinez, R., Hunter, T., and Sudarsanam, S., The protein kinase complanent of the human genome. Science 298,596-601,2(XX) ter Haar, E., Walters, W.P., Pazhanisamy, S. et al.. Kinase chemogenomics targeting the human kinome for target validation and drag discovery. Mini Rev. Med. Chem. 4, 235-253,2004. 

This example reinforces the critical importance of reliable target validation for a given disease. It seems likely that other kinases yet to emerge could impact chronic diseases but not suffer from such unforeseen target/disease related problems. If these are not tyrosine kinases, it may be easier to obtain selective inhibitors to avoid off-target effects while remaining in drug-like chemical space. While research continues into tyrosine kinases for chronic... 

The identification and optimisation of drug-like small molecule inhibitors for kinase targets is a highly competitive arena and given the high level of structural similarity across family members it is unsurprising that the intellectual property landscape has become crowded, especially around some of the more validated targets. The situation is particularly apparent for type I kinase... 

At present, there are two streams of drug discovery activity that could lead to the successful development of a kinase inhibitor as a drug for Plasmodium Malaria, namely in vitro screening activities around validated kinase targets and deconvolution of key targets revealed from the screening of various Malaria Boxes on various stages of the life cycle of the parasite. 

A similar virtual fragment linking approach validated across a variety of different target classes has also been reported [88]. A combination of virtual and experimental (NMR, biochemical) screening methods was employed to identify novel scaffolds for the design of kinase-targeted libraries [89]. 

Aqueous PEG 400 was also used in the formation of 1-aroylmethyl-l,2,3-triazoles 82 from phenacyl bromides, sodium azide, and terminal alk5mes under the copper(II) sulfate/sodium ascorbate catalysis [75]. Similar conditions (room temperature, 30 min) were applied to the syndesis of a variety of 1-substituted 4-aryl-l,2,3-triazoles with yield of 75-90% using the copper(II) sulfate/sodium ascorbate catal5dic system in aqueous PEG 400 [76]. a-Tosyloxy ketones 83, including cyclic, were also successfully adopted as substrates for this reaction (Scheme 49) [77,78]. It was demonstrated that copper(I) iodide could be replaced by the copper(II) sulfate/sodium ascorbate system. Some of the products 84 were reported [78] to inhibit Src kinase, a valid target for the therapy of cancer, acute ischemic stroke, and other diseases. 

In contrast to the DNA damage checkpoint, the mitotic spindle checkpoint is essential for cell viability. Dierefore, targeting kinases of the spindle checkpoint including Bubl, BubRl, and Mpsl might be a valid strategy for anticancer treatment. 

As in all eukaryotic cells, protein kinases play an important role in the life cycle of the kinetoplastids and, as such, are attractive targets. Recent efforts, predominantly through genetic (RNAi) means, have validated a number of kinases as essential for survival of T. brucei, but few have been explored with chemical probes [33-35]. 

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