| Abstract
| - Protein kinase C (PKC) is a complex enzyme system comprised of atleast 11 isozymes thatserves to mediate numerous extracellular signals which generate lipidsecond messengers. Thediscovery of isozyme-selective activators and inhibitors (modulators)of PKC is crucial toascertaining the role of the individual isozymes in physiological andpathophysiological processesand to manipulating their function. The discovery of such smallmolecule modulators of PKCis at present a largely unmet pharmacological need. Herein wedetail our modeling studieswhich reveal how the natural product indolactam V (ILV) and its8-membered ring analogue,the benzolactam 15, bind to the CRD2 activator domain ofPKC. These modeling studies revealthat not all PKC ligands possess a common pharmacophore, and furthersuggest an importantrole of specific hydrophobic contacts in the PKC−ligand interaction.The modeling studiesfind strong experimental support from mutagenesis studies on PKCαthat reveal the crucialrole played by the residues proline 11, leucine 20, leucine 24, andglycine 27. Next, we describethe synthesis of two 8-substituted benzolactams starting froml-phenylalanine and characterizetheir isozyme selectivity; one of the two benzolactams exhibitsimproved isozyme selectivityrelative to the n-octyl-ILV. Lastly, we reportinhibition of cellular proliferation of two differentbreast carcinoma cell lines by the benzolactam 5 and showthat the compound preferentiallydown-regulates PKCβ in both cell lines.
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