Kinase inhibition, inhibitors

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

It is known that protein kinase C can phosphorylate a number of key oxidase components, such as the two cytochrome b subunits and the 47-kDa cytoplasmic factor. This process is prevented by protein kinase C inhibitors such as staurosporine (although it is now recognised that this inhibitor is not specific for protein kinase C), which also inhibits the respiratory burst activated by agonists such as PMA. However, when cells are stimulated by fMet-Leu-Phe, translocation of pAl-phox to the plasma membrane can occur even if protein kinase C activity is blocked - that is, phosphorylation is not essential for the translocation of this component in response to stimulation by this agonist. Similarly, the kinetics of phosphorylation of the cytochrome subunits do not follow the kinetics of oxidase activation, and protein kinase C inhibitors have no effect on oxidase activity elicited by some agonists -for example, on the initiation of the respiratory burst elicited by agonists such as fMet-Leu-Phe (Fig. 6.14). Furthermore, the kinetics of DAG accumulation do not always follow those of oxidase activity. Hence, whilst protein kinase C is undoubtedly involved in oxidase activation by some agonists, oxidase function is not totally dependent upon the activity of this kinase. 

Figure 6.15. Structures of some protein kinase C inhibitors. Staurosporine is a potent inhibitor of protein kinase C, but is not selective. Some derivatives of protein kinase C, such as Ro31-8220 and Ro31-8425, retain a potency similar to that of the parent molecule in protein kinase C inhibition, but are much more specific.

Zhang W, Law RE, Hinton DR, Couldwell WT. (1997). Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. Cancer Lett. 120(1) 31-8. 

There was a time not long ago when researchers were united in the behef that potent, selective kinase inhibition was crucial for the development of safe drugs and that it would be very difficult, if not impossible, to achieve. Conventional wisdom held that the high concentration of cytosoHc ATP (in the milHmolar range) precluded the identification of nanomolar ATP-competitive kinase inhibitors in cell-based assays. Some of these beliefs were grounded... 

The patent literature has reports of many compounds that are claimed to have Aurora kinase inhibition activity but in some of these cases it is not possible to determine whether these compounds are pan-kinase inhibitors or if the compounds are selective for the Aurora kinases. We Umited this review to publications that give specific data for the Aurora kinases and have pertinent selectivity data. Another review has appeared recently [171]. 

Ahn CH, Kong JY, Choi WC, Wang MS (1996) Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor l-(5-isoquinolinesulfonyl)-2-methylpipera2inc (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells. Biochem Pharmacol 52 393-399... 

Ferry DR, Smith A, Malkhandi J, F e DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase 1 clinical trial of the flavonoid quercetin pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2 659-668 Findik D, Song Q, Hidaka H, Lavin M (1995) Protein kinase A inhibitors enhance radiation-induced apoptosis. J Cell Biochem 57 12-21 Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA, 85 582-586 Finkenzeller G, Marme D, Hug H (1992) Inducible overexpression of human protein kinase C in NIH 3T3 fibroblasts results in growth abnormalities. Cell Signall 4 163-177... 

Ikegami Y, Yano S, Nakao K (1996b) Effects of the new selective kinase C inhibitor 4 -N-benzoyl staurosporine on cell cyde distribution and growth inhibition in human small cell lung cancer cells. Arzndm.-Forsch 46 201-204... 

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