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.

本项目资助申请旨在识别抑制双特异性磷酸酶的小分子，如Cdc25B；微管蛋白/微管;或者运动蛋白。JR肟是Curacin A的类似物，直接作用于微管蛋白的秋水仙碱结合位点，经评估发现其无活性。不可逆磷酸酶抑制剂DA-3003-1也被评估，发现具有边际疗效和短半衰期。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。Curran博士的团队已经合成了一些分子，如dictyostatin 1，与disdermolide相关，针对微管蛋白上的紫杉醇结合位点，并将在一年内用于体内试验。该核心负责每年在啮齿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