The Protein Kinase ABC's of Signal Transduction as Targets for Drug Development

Abstract: Signal transduction plays a key regulatory role in the growth and metastatic potential of tumor cells. These signaling pathways form an interconnecting grid that serves to regulate the homeostatic, survival and invasive functions of the cell. Among the key regulatory molecules in these pathways are the serine/threonine-protein kinases A, B and C, also known respectively as cyclic AMP-dependent protein kinase (PKA), Akt (PKB) and protein kinase C (PKC). These protein kinases modulate pathways associated with tumor proliferation, cell survival and multidrug resistance, and at a molecule level are likely to serve as effective targets for drug design. The unique structural features of each protein kinase have been deduced from their crystallographic structures and form unique opportunities for structure-based drug design. In addition, these. protein kinases are potentially important targets for antisense oligonucleotide therapy, and therefore may provide a means of selectively inhibiting tumor proliferation and inducing apoptosis with minimal nonspecific cytotoxicity.