PRECLINICAL EVAL. OF TUBULIN BINDING AGENTS AND DUAL SPEC. PHOSP INHIB. IN RODENT

临床前评估。

• 批准号: 6928836
• 负责人: JULIE L. EISEMAN
• 金额: $ 14.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928836
• 关键词: SCID mouse; antineoplastics; biomedical facility; dosage; drug metabolism; drug screening /evaluation; laboratory mouse; laboratory rat; pharmacokinetics; phosphatase inhibitor; tubulin

This Program Project Grant application is directed at identifying small molecules that inhibit dual specificity phosphatases, such as Cdc25B; tubulin/microtubules; or motor proteins. JR oxime, an analogue of Curacin A directed at the colchicine binding site of tubulin was evaluated and found to be inactive. DA-3003-1, an irreversible phosphatase inhibitor was also evaluated and found to have marginal efficacy and a short halflife. JUN-1111, a dechlorinated analogue of DA-3003-1, is currently being investigated as is another phosphatase inhibitor, 5169131. Molecules such as dictyostatin 1, related to discodermolide, and directed against the paclitaxel binding site on tubulin, have been synthesized by Dr. Curran's group and should be available for in vivo testing within the first year. This Core is responsible for the preclinical evaluation of three, targeted, small molecules each year in rodents. Determination of the maximum tolerated doses of the compounds and efficacy in early xenograft models of prostate, colon, ovarian, and/or breast cancer will be determined first. If the compounds demonstrate activity or if they are the lead compound of a series of analogues of a particular structure, this evaluation will also include development of analytical methods for detection of the compounds in biological matrices and definition of plasma pharmacokinetics after i.v. and other routes of administration of the compounds at their maximum tolerated dose. The effects of the compounds on their molecular targets within the tumor xenografts will also be investigated in additional cohorts of animals included on the pharmacokinetic studies and the efficacy studies. The compounds selected for study in this Core will have been prioritized through the decision network of the Program Project Grant. The results of the studies conducted in this Core will provide information on the metabolism and pharmacokinetics of lead compounds that will be used by the Projects and the bioformatics Core in the modification of structures or the selection of new lead compounds. Data generated in this Core will provide the basis for the support of an IND to the FDA for the most promising lead compounds.

该计划项目授予应用程序旨在鉴定抑制双重特异性磷酸酶的小分子，例如CDC25B；微管蛋白/微管；或运动蛋白。 JR Oxime是针对微管蛋白秋水仙碱结合位点的素素A的类似物，并发现不活跃。还评估了不可逆的磷酸酶抑制剂DA-3003-1，并发现具有边缘疗效和短期寿命。 Jun-1111是DA-3003-1的一种脱氯类似物，目前正在研究，另一种磷酸酶抑制剂是5169131。等分子（例如Dictyostatin 1），与discodermolide，并针对paclitaxel在Tubulin上的结合位点进行了针对curran的组合，并在Curran博士中进行了验证。该核心每年在啮齿动物中对三个有针对性的小分子进行临床前评估。确定最大耐受剂量 将首先确定前列腺，结肠，卵巢和/或乳腺癌早期异种移植模型的化合物和功效。如果这些化合物证明了活性，或者它们是特定结构的一系列类似物的铅化合物，则该评估还将包括开发用于检测生物基质中化合物的分析方法以及静脉注射后血浆药代动力学的定义。以及其他以最大耐受剂量的化合物给药途径。这些化合物对肿瘤异种移植物中其分子靶标的影响也将在药代动力学研究和功效研究中的其他动物中进行研究。选择的化合物 对于此核心的研究，将通过计划项目赠款的决策网络优先考虑。在此核心中进行的研究结果将提供有关铅化合物的新陈代谢和药代动力学的信息，这些化合物将在修饰结构或选择新的铅化合物的修饰中使用，这些化合物和生物形成核心将使用。在此核心中生成的数据将为FDA的支持提供基础，以提供最有前途的铅化合物。