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Preclinical Evaluation:Tubulin Binding Agent & Dual Spec. Phosphatase Inhibitors

临床前评估：微管蛋白结合剂

基本信息

批准号：
7661355
负责人：
JULIE L. EISEMAN
金额：
$ 24.23万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7661355
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Acids Animals Antineoplastic Agents Applications Grants Binding Sites Biochemical Pharmacology Biological Biological Assay Biological Availability Biological Testing Breast Breast Cancer Cell Cancer Etiology Cell Cycle Regulation Chemicals Chemistry Colchicine Colon Colon Carcinoma Curacin A Data Detection Development Dose Drug Kinetics Drug or chemical Tissue Distribution Environment Evaluation Figs - dietary Genus Cola Group Structure High Pressure Liquid Chromatography Human In Vitro Intravenous Investigation Lead Malignant neoplasm of ovary Maximum Tolerated Dose Metabolic Pathway Metabolism Methods Microtubules Modeling Modification Molecular Molecular Target Motor Mus Normal tissue morphology Oral Ovarian Oximes Paclitaxel Phosphoric Monoester Hydrolases Plasma Procedures Production Program Research Project Grants Prostate Proteins Radioactive Radiolabeled Range Research Personnel Rodent Route Sampling Schedule Series Solubility Specificity Structure Techniques Testing Thinking Time Tissues Toxic effect Tubulin Tubulin Binding Agent United States Food and Drug Administration Xenograft Model Xenograft procedure analog analytical method androgen independent prostate cancer base cancer cell chromophore cohort combinatorial detector dictyostatin discodermolide efficacy trial in vivo intravenous administration liquid chromatography mass spectrometry malignant breast neoplasm metabolic abnormality assessment method development novel novel strategies phosphatase inhibitor pre-clinical preclinical study programs radiochemical radiotracer research clinical testing research study small molecule tumor tumor xenograft

项目摘要

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.

该计划项目资助申请旨在鉴定抑制双特异性磷酸酶的小分子，如Cdc 25 B;微管蛋白/微管;或马达蛋白。JR肟，一种针对微管蛋白的秋水仙碱结合位点的Curacin A类似物进行了评价，发现无活性。DA-3003-1是一种不可逆的磷酸酶抑制剂，也进行了评价，发现其疗效有限，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。分子，如dictyostatin 1，与discodermolide相关，并直接针对微管蛋白上的紫杉醇结合位点，已由Curran博士的小组合成，并应在第一年内可用于体内试验。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价。确定最大耐受剂量首先确定化合物在前列腺癌、结肠癌、卵巢癌和/或乳腺癌的早期异种移植模型中的作用和功效。如果化合物表现出活性，或者如果它们是特定结构的一系列类似物的先导化合物，则该评价还将包括开发用于检测生物基质中化合物的分析方法，以及定义以最大耐受剂量静脉内和其他途径给予化合物后的血浆药代动力学。还将在药代动力学研究和疗效研究中纳入的其他动物队列中研究化合物对其在肿瘤异种移植物中的分子靶标的影响。选择的化合物在本核心研究中的研究将通过计划项目补助金的决策网络优先考虑。在本核心中进行的研究结果将提供有关先导化合物代谢和药代动力学的信息，这些信息将由项目和生物合成核心用于结构修饰或选择新的先导化合物。本核心中生成的数据将为向FDA提交最有前途的先导化合物IND提供支持基础。