Recent research into molecular nature of oncogenesis has identified a number of cellular gene (proto-oncogene) products that play key roles as regulators of cellular growth processes and are, therefore, potential targets for the design of novel antitumor agents. The goal of this project is to synthesize and evaluate specific agents designed to inhibit the actions of certain of these proto-oncogene products: the protein-tyrosine kinases. The approach to drug design being used is based on the observation that, in order to function in malignant transformation, some protein-tyrosine kinases must be localized to specific regions of the cell. This localization, which is to the cytoplasmic face of the plasma membrane, is specified in part by a posttranslational modification involving the covalent attachment of a rare fatty acid, myristic acid, to the amino-terminal glycine residue of the kinases via an amide linkage. Specific inhibitors of this relatively rare protein processing event would be expected to interfere with the effects of protein-tyrosine kinases on cell proliferation and transformation.
The specific aims of this research include: 1) design and synthesis of a series of potential inhibitors of protein myristoylation, 2) development of cellular model systems for testing the biological activities of target compounds, 3) delineation of aspects of the mechanism of protein myristoylation to allow the synthesis of further inhibitors, and 4) evaluation of the antitumor activity of inhibitors of protein processing.
