Protein-tyrosine kinases: potential targets for anticancer drug development.

Protein-tyrosine kinases (PTKs) were originally discovered over a decade ago as the dominant transforming components of certain tumor viruses. Since then these enzymes have become recognized as important intracellular mediators of a variety of mitogenic signaling pathways, including those associated with several growth factor receptors. The strong correlation of aberrant or over-expressed PTKs with a number of proliferative diseases has raised the possibility that PTK inhibitors may afford new approaches toward anticancer therapeutics. To address this possibility, potent and specific PTK inhibitors are needed both as pharmacological probes to study PTK-dependent signaling and as potential antiproliferative agents in their own right. De novo design of PTK inhibitors is hampered by a lack of three dimensional information regarding PTKs or the interaction of inhibitors with the enzymes. Motifs for the design of new inhibitors are therefore frequently derived by modification of structural them identified in natural-product screens. Exemplary of this process is the Laboratory of Medicinal Chemistry's program to develop PTK inhibitors based on pharmacophores present in three natural-product PTK inhibitors: lavendustin A, erbstatin and piceatannol. As summarized in this report, such efforts have led to new inhibitors with increased potency and interkinase selectivity. Whether PTK inhibitors will ultimately prove to be useful as antiproliferative therapeutics remains an open question whose answer will be heavily reliant on a cooperative partnership among natural-product and medicinal chemists, pharmacologists and clinicians.