Novel Geldanamycin Analogs as Anti-tumor Agents

这项研究的长期目标是发现在癌症化疗中有用的新的、水溶性的格尔达霉素类似物。17-丙氨基-17-去甲氧基格尔达那霉素(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相关的药物，这些药物是水溶性的，对特定类型的肿瘤细胞具有强大的细胞抑制或细胞毒性作用，这些肿瘤细胞代表由涉及Hsp90的蛋白激酶介导的异常信号引起的癌症。这将通过选择性地改变格尔达霉素及其制成的17-AAG的结构来实现，方法是通过操纵用于格尔达霉素生物合成的聚酮合成酶基因来引入和去除官能团，以提高水溶性和抗肿瘤活性。以这种方式制成的支架将通过化学方法转化为所需的C17取代类似物，并将通过测定与HSP90的相对结合亲和力和依赖于HSP90的蛋白激酶水平的耗尽量来评估其生物学活性。具有微摩尔活性的类似物随后将在体外针对一组已知对热休克蛋白抑制剂有反应的肿瘤细胞株进行测试，以确定用于临床前开发的先导药物。拟议的商业应用：成功地利用基因工程方法制造与格尔达霉素和17-烯丙氨基-17-去甲氧基格尔达霉素相关的新的微生物代谢物，将产生新的17-取代格尔达霉素类似物，可由科山生物科学公司或其他制药公司开发成癌症化疗药物。

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.