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

该计划项目拨款申请旨在识别抑制双重特异性磷酸酶的小分子，如CDC25B；微管/微管；或马达蛋白。针对微管蛋白秋水仙碱结合部位的库拉星A类似物JR肟e进行了评估，发现其没有活性。不可逆磷酸酶抑制剂DA-3003-1也进行了评估，发现其疗效不明显，半衰期较短。JUN-1111是DA-3003-1的脱氯类似物，目前正在研究中，另一种磷酸酶抑制剂5169131也在研究中。Curran博士的团队已经合成了与Discodermolide相关的、针对微管蛋白上紫杉醇结合部位的dictyostatin 1等分子，并应在第一年内可用于体内测试。该中心负责每年对啮齿动物体内的三个靶向小分子进行临床前评估。最大耐受量的测定 将首先确定前列腺癌、结肠癌、卵巢癌和/或乳腺癌早期异种移植模型中的化合物和疗效。如果化合物显示出活性，或者如果它们是一系列特定结构类似物的先导化合物，这项评估还将包括开发分析方法以检测生物基质中的化合物，并定义静脉注射后的血浆药代动力学。以及以其最大耐受量给药的其他途径。这些化合物对肿瘤移植瘤内分子靶点的影响也将在包括药代动力学研究和疗效研究在内的其他动物队列中进行研究。选定的化合物 将通过计划项目赠款的决策网络确定在这一核心进行研究的优先顺序。在该核心进行的研究结果将提供有关先导化合物的新陈代谢和药代动力学的信息，这些先导化合物将被项目和生物信息学核心用于修改结构或选择新的先导化合物。在这个核心中产生的数据将为IND向FDA提供最有希望的先导化合物的支持提供基础。

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.