The underlying hypothesis of this proposal is that inhibitors of heparan sulfate? biosynthesis will slow tumor growth. Genetic and pharmacological data has validated heparan sulfate as a novel anti-cancer target. This proposal describes a drug discovery program that uses 2 high throughput cell-based screens to identify small molecule inhibitors of heparan sulfate biosynthesis. The assays are based on resistance to toxins, whose mode of action depends on binding to cell surface heparan sulfate. Thus, an agent that inhibits heparan sulfate renders the cells resistant to a toxin, which can be readily scored by continued cell growth in the presence of toxin and inhibitor. Both assays have been validated through their ability to detect partial inhibition of heparan sulfate by chlorate, an inhibitor of macromolecular sulfation. This proposal requests funds to run the high throughput discovery screen and to characterize the lead molecules that emerge. In vitro testing of the effects on growth factor signaling will be used to determine if the compounds represent viable drug development candidates. Promising leads will be candidates for further development as novel anti-cancer drugs in a Phase II SBIR application. The goal of this research is to discover drugs that inhibit heparan sulfate to block tumor growth. If compounds discovered in the screen block tumor growth in the proposed in vitro tests, analogs based their chemical structures will be developed and tested in animal models in a Phase II application. Drugs identified through this research could provide a new approach to fighting cancer. ?
