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: 6738936
• 负责人: CHARLES R HUTCHINSON
• 金额: $ 37.5万
• 依托单位: KOSAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738936
• 关键词: analog; antineoplastic antibiotics; chemical structure; chemical synthesis; drug design /synthesis /production; drug discovery /isolation; heat shock proteins; pharmacokinetics; protein kinase; quinones; water solubility

DESCRIPTION (provided by applicant): The long-range goal of our research program is to discover novel, more potent water soluble geldanamycin analogs and to develop one of them into a useful antitumor drug. 17-Allylamino-17-desmethoxygeldanamycin (17-AAG), the first Hsp90 inhibitor to enter Phase I clinical trials for cancer chemotherapy, has shown higher blood levels and lesser liver toxicity than geldanamycin. We will seek compounds related to 17-AAG and its more water soluble analog, 17-(2'-dimethylamino)ethylamino-17-desmethoxygeldanamycin (17-DMAG), independently discovered at Kosan Biosciences and the National Cancer Institute. In Phase II research, we aim to discover analogs with satisfactory watersolubility that have better pharmacokinetics and pharmacodynamics, and greater potency or lesser unwanted toxicity than either of these drugs. This will be achieved by selectively altering the chemical structure of geldanamycin through manipulation of the geldanamycin biosynthesis genes, following successful proof-of-concept experiments carried out in our Phase I program. Microbial processes will be developed to provide end products or starting materials for synthetic modification, enabling the preparation and biological testing of "second generation" geldanamycin analogs through pursuit of the following Specific Aims. (1) Optimize the microbial process for production of the best "desmethyl, desmethoxy or hydroxygeldanamycin scaffold" discovered by PKS gene engineering in Phase I. (2) Develop microbial processes to make the following compounds: 11-O-methyl-17R-geldanamycin, 15-hydroxy-17R-geldanamycin and 21-deshydroxy-17R-geldanamycin. (3) Identify a second generation antitumor drug development candidate by synthesis of specific geldanamycin analogs and determination of the following biological properties: Binding to Hsp90, Plasma protein binding, Cellular uptake, Effect on depletion of Hsp90 client proteins, Inhibition of drug metabolizing CYP450 enzymes, Cytotoxic activity in vitro, Antitumor activity in mouse tumor model(s), Pharmacokinetics (PK), pharmacodynamics (PD) and other characteristics of absorption, distribution, metabolism and excretion (ADME) through preclinical studies carried out in vitro and in animals.. By these studies, we will identify the best geldanamycin analog to carry forward into drug development, with the eventual aim of filing and IND application and performing clinical trials.

描述（由申请人提供）：我们研究项目的长期目标是发现新的，更有效的水溶性格尔达霉素类似物，并将其中一种开发成有用的抗肿瘤药物。17-烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG）是首个进入癌症化疗I期临床试验的热休克蛋白90抑制剂，其血药浓度高于格尔达霉素，肝毒性较小。我们将寻找与17- aag及其水溶性类似物17-（2'-二甲氨基）乙胺-17-去甲氧基格尔达霉素（17- dmag）相关的化合物，17-（2'-二甲氨基）乙胺-17-去甲氧基格尔达霉素（17- dmag）是由Kosan生物科学公司和国家癌症研究所独立发现的。在II期研究中，我们的目标是发现具有令人满意的水溶性的类似物，具有更好的药代动力学和药效学，并且比这些药物中的任何一种具有更高的效力或更少的有害毒性。这将通过操纵格尔达霉素生物合成基因有选择地改变格尔达霉素的化学结构来实现，在我们的I期项目中进行了成功的概念验证实验。将开发微生物工艺，为合成修饰提供最终产品或起始材料，通过追求以下具体目标，使“第二代”格尔达霉素类似物的制备和生物测试成为可能。(1)优化微生物工艺，生产PKS基因工程一期发现的最佳“去甲基、去甲氧基或羟基格尔达霉素支架”。(2)开发微生物工艺，制备以下化合物：11- o -甲基- 17r -格尔达霉素、15-羟基- 17r -格尔达霉素和21-去羟基- 17r -格尔达霉素。(3)通过合成特异的格尔达霉素类似物并测定以下生物学特性，确定第二代抗肿瘤药物开发候选药物：与Hsp90结合、血浆蛋白结合、细胞摄取、对Hsp90客户蛋白耗损的影响、药物代谢CYP450酶的抑制、体外细胞毒活性、小鼠肿瘤模型抗肿瘤活性、药代动力学（PK）、药效学（PD）等吸收、分布、代谢和排泄特性（ADME）的临床前研究。通过这些研究，我们将确定最佳的格尔达霉素类似物进行药物开发，最终目标是提交和IND申请并进行临床试验。