LACK OF AN EFFECT OF NOVEL INHIBITORS WITH HIGH SPECIFICITY FOR PROTEIN-KINASE-C ON THE ACTION OF THE PHORBOL ESTER 12-O-TETRADECANOYLPHORBOL-13-ACETATE ON MOUSE SKIN IN-VIVO

The inhibitory effects of three novel staurosporine-derived compounds were tested with five different types of protein kinases, including pr otein kinase C (PKC). IC50 values of two of these compounds were found to be 300 to >5(a00 times lower for PKC alpha beta gamma (a mixture o f the PKC isoenzymes alpha, beta and gamma) than for any of the other protein kinases. The inhibitory action of the most selective inhibitor was tested also with the Ca2+-unresponsive PKC isoenzyme delta and wa s found to suppress PKC alpha beta gamma and PKC delta differentially. The highly specific PKC inhibitors are active both in cell culture an d in vivo. They inhibit the PKC-catalyzed phosphorylation of the speci fic PKC substrate MARCKS in Swiss-3T3 fibroblasts and the okadaic acid -induced edema of the mouse ear. However, the more complex biological processes triggered by the phorbol ester 12-O-tetradecanoylphorbol-13- acetate in mouse skin, such as inflammation, stimulation of cellular h yperproliferation and tumor promotion, remain largely unaffected upon topical application of these compounds.