Enzyme Targets, Apoptosis and Purine Metabolism

描述：(申请人提供) 许多来自自然的药物呈现出复杂的分子结构，导致 与细胞靶标的不同程度的特定相互作用。理性的人 新癌症疗法的选择和实施将得到改善，如果 评估所有药物靶标相互作用的基础都是可用的。这 提案将解决多个药物靶点对 安沙霉素类抗肿瘤药物。我们的努力将集中在分子上 实验性乳腺癌药物L7-烯丙氨基-17-的靶点(S) 去甲氧基格尔达那霉素(17-AAG)。 苯喹类阿霉素格尔达霉素(GA)和除草剂A 研究了九烯醇基自由基醇的抗增殖作用。 显示细胞抑制和细胞毒活性的活性。最新研究 预测细胞毒性的作用模式与抑制作用有关 细胞伴侣Hsp90或其同系物Grp94。这项提议面临挑战 假设Hsp90是诱导肿瘤细胞死亡的主要方式 由GA提供。 我们最近发现了该药物的一个高亲和力结合位点。 格尔达霉素对从头合成嘌呤生物合成途径中一种酶的影响 ADE2.彻底分析这种相互作用在肿瘤细胞和其 药物作用的后果将为使用这一方法提供科学依据 关于这类药物未来应用的信息。一份详细的生化报告 人ADE2蛋白在肿瘤细胞中的表达及其生物学特性 GA对其抑制作用的分子细节研究 建议。这些研究将评估ADE2是否是癌症的合适靶点 化疗和如果嘌呤耗竭是诱导 细胞凋亡。这些研究构成了一种新的生物进化方法 新嘌呤代谢中抗癌药物靶点的展望。一个 对人类生化作用和调节的机械性理解 肿瘤细胞中的ADE2蛋白将是这一分析的基本基础。

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.