Protein kinase inhibition of clinically important staurosporine analogues

Abstract

Covering: up to the end of 2009

The isolation in 1977 of the microbial alkaloid staurosporine inaugurated research into several distinct series of related natural and synthetic compounds. This has especially included research into applications as anticancer drugs, beginning with the observation of low nanomolar inhibition of protein kinases. At present, several staurosporine cognates are in advanced clinical trials as anticancer agents, with the potential to join the 10 other protein kinase inhibitors now approved for clinical use. Staurosporine is a broadly selective and potent protein kinase inhibitor, with submicromolar binding to the vast majority of the protein kinases tested, and binding most of them more tightly than 100 nM. Crystal structures have shown the extended buried surface area interactions between the protein kinase adenine binding site and the extended aromatic plane of the inhibitor, together with protein–saccharide interactions in the ribose binding site. Together with structures of closely related analogues, there are now some 70 X-ray crystal structures in the Protein Data Bank that enable analysis of target binding properties of the clinical compounds. In this manuscript we review the discovery of these compounds, revisit crystal structures and review the observed interactions. These support the interpretation of kinase selectivity profiles of staurosporine and its analogues, including midostaurin (PKC412), for which a co-crystal structure is not yet available. Further, the mix of purely natural, biosynthetically and chemically modified compounds described here offer insights into prospects and strategies for drug discovery via bioprospecting.