| 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 ccids 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. |
