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: 6875620
• 负责人: GARY W ASHLEY
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875620
• 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）：我们研究计划的长期目标是发现新的、更有效的水溶性格尔德霉素类似物，并将其中之一开发成有用的抗肿瘤药物。17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）是第一个进入癌症化疗I期临床试验的Hsp 90抑制剂，其血液浓度比格尔德霉素更高，肝脏毒性更小。我们将寻找与17-AAG及其更水溶性的类似物17-（2 '-二甲氨基）乙氨基-17-去甲氧基格尔德霉素（17-DMAG）相关的化合物，这些化合物是在Kosan Biosciences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，这些类似物具有更好的药代动力学和药效学，以及比这些药物更大的效力或更小的有害毒性。这将通过操纵格尔德霉素生物合成基因选择性地改变格尔德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，以提供最终产品或合成修饰的起始物料，通过追求以下特定目标，实现“第二代”格尔德霉素类似物的制备和生物学检测。(1)优化微生物工艺生产PKS基因工程I期发现的最佳“去甲基、去甲氧基或羟基格尔德霉素支架”。(2)开发微生物工艺以制备以下化合物：11-O-甲基-17R-格尔德霉素、15-羟基-17R-格尔德霉素和21-去羟基-17R-格尔德霉素。(3)通过合成特异性格尔德霉素类似物并测定以下生物学特性，鉴定第二代抗肿瘤药物开发候选药物：与Hsp 90的结合，血浆蛋白结合，细胞摄取，对Hsp 90客户蛋白消耗的影响，药物代谢CYP 450酶的抑制，体外细胞毒性活性，小鼠肿瘤模型中的抗肿瘤活性，药代动力学（PK），通过在体外和动物中进行的临床前研究，对药效学（PD）和吸收、分布、代谢和排泄（ADME）的其他特征进行了研究。通过这些研究，我们将确定最好的格尔德霉素类似物进行药物开发，最终的目的是备案和IND申请和进行临床试验。