VALIDATION AND OPTIMIZATION OF TUBULIN TARGETED DRUGS

微管蛋白靶向药物的验证和优化

• 批准号: 6020329
• 负责人: BILLY W DAY
• 金额: $ 13万
• 依托单位: PROLX PHARMACEUTICALS, LP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-08 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6020329
• 关键词: antineoplastics; athymic mouse; biological products; breast neoplasms; cyclopropanes; drug design /synthesis /production; drug discovery /isolation; high performance liquid chromatography; immunosuppressive; lactones; mass spectrometry; molecular dynamics; nuclear magnetic resonance spectroscopy; ovary neoplasms; paclitaxel; tubulin

Paclitaxel and the vinca alkaloids represent important chemotherapeutics in the treatment of cancer. These drugs, however, exhibit undesirable side effects and have limiting physicochemical properties. This project will discover potential drug leads that overcome these limitations. The approaches to be used are synthesis, computational screening, high- throughput assays for biological effects, and nude mouse xenograft antitumor studies. The lead compounds are 1) structurally simple, low toxicity dichlorocyclopropanes, and 2) (+)-discodermolide. The dichlorocyclopropanes are essentially non-toxic to rodents (LD50's of > 3 g/kg), yet active against human breast, ovarian and prostate tumor cells in vitro, and rat mammary carcinomas in vivo. Computationally designed derivatives (32) will be synthesized and tested for improved potency. Using this group's extensive computational chemistry capabilities, QSAR models for microtubule perturbation have been validated. In this way the action of (+)-discodermolide was discovered. It has subsequently been found to be the most potent microtubule stabilizing agent known to date. In this project, not only will sufficient quantities of (+)-discodermolide for animal testing be prepared, but also a series of 18 simplified analogs, based on the QSAR analyses, will be synthesized. Finally, a virtual screening effort with the QSAR systems has identified 200 novel chemicals within the untested portion of the NCI DTP repository predicted to have paclitaxel-like properties. These will be obtained and screened in the in vitro assays. In the end, the two most effective agents discovered from the above approaches will then be screened for in vivo antitumor activity. PROPOSED COMMERCIAL APPLICATIONS: This project will discover potential drug leads that overcome undesirable side effects and costly methods of administration which afflict current therapies against breast and prostate cancers. Moreover, it will validate the computational chemistry approach to drug discovery.

紫杉醇和长春花生物碱是治疗癌症的重要化疗药物。 然而，这些药物表现出不良副作用并且具有有限的物理化学性质。该项目将发现克服这些限制的潜在药物先导物。使用的方法包括合成、计算筛选、生物效应的高通量测定以及裸鼠异种移植抗肿瘤研究。先导化合物是 1) 结构简单、低毒性的二氯环丙烷和 2) (+)-discodermolide。 二氯环丙烷对啮齿动物基本上无毒（LD50 > 3 g/kg），但在体外对人类乳腺癌、卵巢和前列腺肿瘤细胞以及体内大鼠乳腺癌具有活性。将合成并测试计算设计的衍生物（32）以提高效力。利用该小组广泛的计算化学能力，微管扰动的 QSAR 模型已得到验证。以这种方式发现了(+)-discodermolide的作用。随后发现它是迄今为止已知的最有效的微管稳定剂。在该项目中，不仅将制备足够数量的 (+)-discodermolide 用于动物试验，还将根据 QSAR 分析合成一系列 18 种简化类似物。最后，使用 QSAR 系统进行的虚拟筛选工作在 NCI DTP 存储库的未经测试部分中鉴定出了 200 种新型化学物质，预计它们具有类似紫杉醇的特性。这些将在体外测定中获得和筛选。最后，将筛选从上述方法中发现的两种最有效的药物的体内抗肿瘤活性。拟议的商业应用：该项目将发现潜在的先导药物，克服不良副作用和昂贵的给药方法，这些方法困扰着目前乳腺癌和前列腺癌的治疗。此外，它将验证药物发现的计算化学方法。