Enzyme Targets, Apoptosis and Purine Metabolism

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DESCRIPTION: (provided by applicant) Many drugs from nature present complex molecular architectures that result in varied degrees of specific interactions with cellular targets. The rational selection and implementation of new cancer therapies would be improved if a basis for assessing all the drug target interactions were available. This proposal will address the importance of multiple drug targets for the ansamycin class of antitumor agents. Our efforts will focus on the molecular target(s) for the experimental breast cancer drug l7-allylamino-17- demethoxygeldanamycin (17-AAG). The benzoquinoid ansamycins geldanamycin (GA) and herbimycin A and the nonapolyketide radicicol have been investigated for their antiproliferative activity showing both cytostatic and cytotoxic activities. Recent studies predict the mode of action for the cytotoxicity is associated with inhibition of the cellular chaperone Hsp90 or its homolog Grp94. This proposal challenges the assumptions that Hsp90 is a primary mode for induction of tumor cell death by GA. We have recently identified a high-affinity binding site for the drug geldanamycin on an enzyme in the de novo purine biosynthetic pathway called ADE2. A thorough analysis of this interaction in tumor cells and its consequences for drug action will provide the scientific basis for using this information in future applications of this drug class. A detailed biochemical characterization of the human ADE2 protein from tumor cells and an investigation of the molecular details dictating its inhibition by GA are proposed. These studies will assess if ADE2 is a suitable target for cancer chemotherapy and if purine depletion is a critical step in the induction of apoptosis. The studies constitute a biorational approach toward a new perspective on targets for anticancer drugs in de novo purine metabolism. A mechanistic understanding of the biochemical role and regulation of the human ADE2 protein in tumor cells will be a fundamental basis for this analysis.