Robert L. Dow Pages 192 - 203 ( 12 )
Protein kinase C (PKC), a member of the serine/threonine family of protein kinases, is an integral part of cellular signal transduction. There is mounting evidence that inappropriate activation of PKC may be responsible for a number of disease states. Potent, selective inhibitors of PKC could serve as valuable tools for def,lning these signaling pathways, as well as, for the treatment of diseases mediated through aberrant PKC activity. Several mechanistically-distinct classes of inhibitors have been identified which potently and selectively suppress PKC activity. The most advanced and promising of these agents are Go-6976 and Ro-32-0432, which arose from optimization studies on staurosporine, an indolecarbazole-based natural product. Though these compounds inhibit PKC competitively with respect to nucleotide cofactor, they exhibit little inhibitory activity against a range of other nucleotide-dependent enzymes. More modest advances have begun to be made with respect to selective inhibition of the various PKC isozymes. This review will update efforts directed towards the discovery of inhibitors of PKC, with a focus on the associated selectivity parameters.