Novel Geldanamycin Analogs as Anti-tumor Agents

作为抗肿瘤剂的新型格尔德霉素类似物

• 批准号: 6484983
• 负责人: CHARLES R HUTCHINSON
• 金额: $ 10万
• 依托单位: KOSAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-09 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6484983
• 关键词: antineoplastic antibiotics; chemical structure; chemical synthesis; drug design /synthesis /production; drug discovery /isolation; heat shock proteins; protein kinase; quinones; water solubility

The long-range goal of the research is to discover novel, water soluble geldanamycin analogs useful in cancer chemotherapy. 17-Allyamino-17- demethoxygeldanamycin (17-AAG) is in clinical trials. To overcome important shortcomings of this drug, we will seek drugs related to 17- AAG that are water soluble and exhibit potent cytostatic or cytotoxic effects on specific types of tumor cells representing cancers caused by aberrant protein kinase mediated signalling involving Hsp90. This will be achieved by selectivity altering the structure of geldanamycin and the 17-AAG made from it through manipulation of the polyketide synthase genes for geldanamycin biosynthesis to both introduce and remove functionality to enhance water solubility and anti-tumor activity. Scaffolds made in this way will be converted by chemical methods to the desired C17-substituted analogs, and their biological activity will be evaluated by determining relative binding affinity to Hsp90 and the amount of depletion of the level of an HSP90-dependent protein kinase. Analogs with <1 micromolar activity will then be tested in vitro against a panel of tumor cell lines known to respond to Hsp inhibitors to identify lead drugs for pre-clinical development. PROPOSED COMMERCIAL APPLICATIONS: Successful use of the genetic engineering approach to make noel microbial metabolites related to geldanamycin and 17-allyamino-17- demethoxygeldanamycin will result in new 17-substituted geldanamycin analogs that can be developed into cancer chemotherapy drugs by Kosan Biosciences or other pharmaceutical firms.

该研究的长期目标是发现可用于癌症化疗的新型水溶性格尔德霉素类似物。 17-烯丙胺-17-去甲氧基格尔德霉素 (17-AAG) 正在进行临床试验。为了克服这种药物的重要缺点，我们将寻找与 17-AAG 相关的水溶性药物，并对特定类型的肿瘤细胞表现出有效的细胞抑制或细胞毒性作用，这些肿瘤细胞代表由涉及 Hsp90 的异常蛋白激酶介导的信号传导引起的癌症。这将通过选择性改变格尔德霉素和由其制成的17-AAG的结构来实现，通过操作用于格尔德霉素生物合成的聚酮合酶基因来引入和去除功能以增强水溶性和抗肿瘤活性。以这种方式制备的支架将通过化学方法转化为所需的C17取代的类似物，并且将通过测定与Hsp90的相对结合亲和力和HSP90依赖性蛋白激酶水平的消耗量来评估它们的生物活性。然后，活性<1微摩尔的类似物将在体外针对一组已知对Hsp抑制剂有反应的肿瘤细胞系进行测试，以确定用于临床前开发的先导药物。拟议的商业应用：成功利用基因工程方法制造与格尔德霉素和17-烯丙氨基-17-去甲氧基格尔德霉素相关的noel微生物代谢物将产生新的17-取代格尔德霉素类似物，可由Kosan Biosciences或其他制药公司开发成癌症化疗药物公司。