Small Molecule Inhibitors of the WIP1 Oncogene

WIP1 癌基因的小分子抑制剂

基本信息

批准号：
6681979
负责人：
RICHARD J AUSTIN
金额：
$ 25万
依托单位：
TULARIK, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-11 至 2004-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6681979
关键词：
SCID mouse antineoplastics apoptosis breast neoplasms cell proliferation combinatorial chemistry drug design /synthesis /production enzyme activity enzyme inhibitors enzyme linked immunosorbent assay gene expression high throughput technology mitogen activated protein kinase neoplasm /cancer chemotherapy neoplasm /cancer pharmacology nuclear magnetic resonance spectroscopy oncogenes p53 gene /protein polymerase chain reaction prostate neoplasms tissue /cell culture western blottings

SCID mouse antineoplastics apoptosis breast neoplasms cell proliferation combinatorial chemistry drug design /synthesis /production enzyme activity enzyme inhibitors enzyme linked immunosorbent assay gene expression high throughput technology mitogen activated protein kinase neoplasm /cancer chemotherapy neoplasm /cancer pharmacology nuclear magnetic resonance spectroscopy oncogenes p53 gene /protein polymerase chain reaction prostate neoplasms tissue /cell culture western blottings

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项目摘要

DESCRIPTION (provided by applicant): Our goal is to develop a drug that inhibits the oncogene WIP1 (PPM1D). We previously determined that WlP1 is amplified at the DNA level in breast tumors and is overexpressed at the RNA level in breast and metastatic prostate tumors [10]. Additional studies have shown that WlP1 overexpression promotes cell proliferation and protects cells from apoptosis, properties consistent with a role in cancer [3, 6, 10, 17]. We have completed a high-throughput screen which identified compounds that inhibit Wip1 phosphatase activity in vitro. In this grant we propose to use these inhibitory compounds to generate leads for creating a Wip1-specific anti-cancer drug. First, the inhibitors will be biochemically characterized to rank their potency, to determine specificity for Wip1 compared to other phosphatases, and to investigate the mechanism of enzyme inhibition. Second, assays will be developed for testing the ability of these compounds to inhibit Wip1 function in cultured cells. Third, medicinal chemistry will be initiated to develop compounds that have increased potency, specificity, and cell-based activity. Finally, these compounds, including those obtained from medicinal chemistry, will be tested for their ability to inhibit tumor formation in mice. Assuming all of these efforts are successful, this work will result in a pre-clinical candidate for a novel anti-cancer drug.

描述（由申请人提供）：我们的目标是开发一种抑制癌基因WIP1（PPM1D）的药物。我们以前确定WLP1在乳腺肿瘤的DNA水平上放大，并在乳腺和转移性前列腺肿瘤的RNA水平过表达[10]。其他研究表明，WLP1的过表达促进细胞增殖并保护细胞免受凋亡，特性与癌症中的作用一致[3,6,10,17]。我们已经完成了一个高通量屏幕，该屏幕鉴定出在体外抑制WIP1磷酸酶活性的化合物。在这笔赠款中，我们建议使用这些抑制性化合物来产生铅来创建WIP1特异性抗癌药。首先，将抑制剂在生化上表征以对其效力进行排名，以确定与其他磷酸酶相比的WIP1的特异性，并研究酶抑制的机理。其次，将开发用于测试这些化合物抑制培养细胞中WIP1功能的能力的测定。第三，将启动药物化学来开发具有提高效力，特异性和基于细胞活性的化合物。最后，这些化合物，包括从药物化学中获得的化合物，将测试其抑制小鼠肿瘤形成的能力。假设所有这些努力都是成功的，这项工作将导致新型抗癌药物的临床前候选者。