Isoform-selectivity of PKC Inhibitors Acting at the Regulatory and Catalytic Domain of Mammalian PKC-, -&bgr;I, -&dgr;, -&eegr; and -&zgr;

Author： Saraiva Lucília Fresco Paula Pinto Eugénia Gonçalves Jorge

Publisher： Informa Healthcare

ISSN： 1475-6366

Source： Journal of Enzyme Inhibition and Medicinal Chemistry, Vol.18, Iss.6, 2003-12, pp. : 475-483

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Abstract

The aim of the present study was to compare the potency of a series of widely used PKC inhibitors acting either at the regulatory (NPC 15437, tamoxifen and d-sphingosine) or at the catalytic domain (Ro 32-0432, chelerythrine and rottlerin) on individual mammalian PKC isoforms of the classical ( and &bgr;I), novel (&dgr; and &eegr;) and atypical (&zgr;) PKC families, using the yeast phenotypic assay, in order to determine their isoform-selectivity. The PKC inhibitors studied presented differences in their ability to reduce the effect of the appropriate PKC activator (estimated as EC₅₀ ratios) which was interpreted as an index of PKC inhibitory potency. In general, the more marked inhibition was observed on novel PKC isoforms, particularly on PKC-η. This study indicates promising isoform-selectivity of some PKC inhibitors, namely NPC 15437 for PKC-η or rottlerin for both novel PKC isoforms. It also suggests that the PKC domain involved in the inhibition does not seem to be relevant for the potency and isoform-selectivity of PKC inhibitors.