Novel Geldanamycin Analogs as Anti-Tumor Agents

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达霉素类似物，并将其中一种开发为有用的抗肿瘤药物。17-烯丙氨基-17-去甲氧基格尔达霉素(17-AAG)是第一个进入癌症化疗I期临床试验的Hsp90抑制剂，已显示出比格尔达霉素更高的血液浓度和更低的肝脏毒性。我们将寻找与17-AAG及其更水溶性类似物17-(2‘-dimethylamino)ethylamino-17-desmethoxygeldanamycin(17-DMAG)相关的化合物，这些化合物是由kosan生物科学公司和国家癌症研究所独立发现的。在第二阶段的研究中，我们的目标是发现具有令人满意的水溶性的类似物，这些类似物具有比这两种药物更好的药代动力学和药效学，以及更大的效力或更少的有害毒性。这将通过在我们的第一阶段计划中成功地进行概念验证实验之后，通过操纵格尔达霉素生物合成基因来选择性地改变格尔达霉素的化学结构来实现。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)优化微生物生产工艺，以生产一期PKS基因工程发现的最佳“脱甲基、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-脱羟基-17R-格尔达霉素。(3)通过体外和动物的临床前研究，通过对格尔达霉素类似物的合成和对HSP90结合、血浆蛋白结合、细胞摄取、对HSP90客户蛋白耗竭的影响、对药物代谢酶450酶的抑制、体外细胞毒活性、小鼠肿瘤模型(S)的抗肿瘤活性、药代动力学(PK)、药效学(PD)等吸收、分布、代谢和排泄特性(ADME)的测定，确定第二代抗肿瘤药物开发候选药物。通过这些研究，我们将确定最好的格尔达霉素类似物应用于药物开发，最终目标是提交申请和IND申请并进行临床试验。

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.