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Therapeutic potential of protein kinase C inhibitors
D Bradshaw1, C H Hill, J S Nixon
1Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., UK.
Abstract:
The serine/threonine protein kinase, protein kinase C (PKC) is a family of closely related isoforms which are physiologically activated by diacylglycerol generated by the binding of a variety of agonists to their cellular receptors. Free fatty acids may also play a role in activating PKC. The enzyme apparently mediates a wide range of signal transduction processes in cells and, therefore, inhibitors directed selectively against PKC may have wide-ranging therapeutic potential. This review highlights the evidence that inappropriate activation of PKC occurs in a number of disease states. Such evidence, however, is often seriously flawed because it relies on the use of phorbol esters, which are potent and direct PKC activators but may not mimic the physiological triggering of the enzyme in cells, or on the use of non-selective protein kinase inhibitors such as H7 and staurosporine. A new generation of bis-indolylmaleimides, derived from the lead provided by staurosporine, shows a high degree of selectivity for PKC over closely related protein kinases and such agents may provide more appropriate tools to investigate the role of PKC in cellular processes.
Insights
Protein Kinase C (PKC) plays a role in cell signaling. New selective inhibitors are crucial for accurately studying PKC
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Protein Kinase C (PKC) is a family of serine/threonine kinases involved in diverse cellular signal transduction pathways.
- Physiological activation of PKC typically occurs via diacylglycerol, generated by receptor-ligand interactions, with potential roles for free fatty acids.
- Dysregulation of PKC activity has been implicated in various disease states, suggesting therapeutic potential for selective inhibitors.
Purpose of the Study:
- To review the evidence linking PKC dysregulation to disease states.
- To critically evaluate the methodologies used to study PKC activation and inhibition.
- To introduce novel, selective PKC inhibitors as improved research tools.
Main Methods:
- Review of existing literature on PKC activation and inhibition.
- Analysis of the limitations of commonly used research tools, such as phorbol esters and non-selective inhibitors (H7, staurosporine).
- Introduction of a new class of selective bis-indolylmaleimide inhibitors.
Main Results:
- Much of the evidence for PKC involvement in disease is flawed due to the use of non-specific activators or inhibitors.
- Phorbol esters and non-selective inhibitors may not accurately reflect physiological PKC activation.
- Bis-indolylmaleimides demonstrate high selectivity for PKC over related kinases.
Conclusions:
- Selective inhibition of PKC is essential for accurate investigation of its role in cellular processes and disease.
- The limitations of current research tools necessitate the development and use of more specific agents.
- Bis-indolylmaleimides represent a promising new generation of tools for studying PKC function.