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.

该计划项目拨款申请旨在鉴定抑制双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 肟（Curacin A 的类似物）针对微管蛋白秋水仙碱结合位点进行了评估，发现其无活性。还对不可逆磷酸酶抑制剂 DA-3003-1 进行了评估，发现其疗效有限且半衰期短。 JUN-1111 是 DA-3003-1 的脱氯类似物，目前正在研究另一种磷酸酶抑制剂 5169131。诸如 dictyostatin 1 等分子与 discodermolide 相关，针对微管蛋白上的紫杉醇结合位点，已由以下公司合成： Curran 博士的团队应该可以在第一年内进行体内测试。该核心负责每年在啮齿类动物中对三种靶向小分子进行临床前评估。最大耐受剂量的测定 首先将确定前列腺癌、结肠癌、卵巢癌和/或乳腺癌的早期异种移植模型中的化合物和功效。如果这些化合物表现出活性或者它们是一系列特定结构类似物的先导化合物，则该评估还将包括开发用于检测生物基质中的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。以及以最大耐受剂量施用化合物的其他途径。这些化合物对其肿瘤异种移植物内分子靶标的影响也将在药代动力学研究和功效研究中包括的其他动物组中进行研究。所选化合物 该核心研究将通过计划项目补助金的决策网络进行优先排序。该核心中进行的研究结果将提供有关先导化合物的代谢和药代动力学的信息，这些信息将由项目和生物信息学核心用于结构修饰或新先导化合物的选择。该核心生成的数据将为 FDA 支持最有前途的先导化合物的 IND 提供基础。