Enzyme Targets, Apoptosis and Purine Metabolism

描述：（申请人提供） 许多来自自然界的药物呈现复杂的分子结构， 不同程度的与细胞靶点的特异性相互作用。 合理 新的癌症治疗方法的选择和实施将得到改善， 评估所有药物靶点相互作用的基础可用。 这 该提案将解决多个药物靶点的重要性 安莎霉素类抗肿瘤剂。 我们的努力将集中在分子上 实验性乳腺癌药物17-烯丙基氨基-17- 去甲氧基格尔德霉素（17-AAG）。 苯醌类安莎霉素格尔德霉素（GA）和除莠霉素A以及 已经研究了九聚酮根赤霉素的抗增殖活性， 显示细胞生长抑制和细胞毒活性的活性。最近的研究 预测细胞毒性的作用方式与抑制有关 细胞伴侣蛋白Hsp 90或其同系物Grp 94。该提案挑战 假设Hsp 90是诱导肿瘤细胞死亡的主要模式， 通过GA。 我们最近发现了一个药物的高亲和力结合位点 格尔德霉素作用于嘌呤生物合成途径中的一种酶， ADE2。深入分析肿瘤细胞中的这种相互作用及其 药物作用的后果将提供科学依据， 这类药物的未来应用信息。详细的生化分析 来自肿瘤细胞的人ADE 2蛋白的表征和 的分子细节指示其抑制GA的调查是 提出了这些研究将评估ADE 2是否是癌症的合适靶点 如果嘌呤耗竭是诱导化疗的关键步骤， 凋亡这些研究构成了一种新的生物理性方法， 嘌呤从头代谢中抗癌药物靶点的观点。一 对人体生物化学作用和调节的机械理解 肿瘤细胞中的ADE 2蛋白将是这种分析的基本基础。

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.