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Pim 1 protein kinase as a target for drug discovery

Pim 1 蛋白激酶作为药物发现的靶标

基本信息

批准号：
6922674
负责人：
Andrew S Kraft
金额：
$ 4.77万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2006-03-31
项目状态：
已结题

项目摘要

The goals of this proposal are to validate the hypothesis that the protein kinase Pim-1 is a potential target for chemotherapy development. Pim-1 protein kinase was cloned as a retroviral insertion point in a screen for genes that enhance tumorigenesis by c-myc. The observation that transgenic mice that carry this protein have an elevated incidence of T- cell lymphomas, and that these mice are extremely sensitive to carcinogen treatment, further suggests that Pim is important in tumorigenesis. Our results demonstrate that the Pim-1 protein kinase is a nuclear enzyme that regulates the levels of bcl-2 mRNA and mdm2 protein, suggesting that Pim-1 may effect the function of p53. The Aims of this proposal are to: (1) determine whether Pim activity is elevated in various tumor types, (2) examine whether Pim regulates specific pathways necessary for tumorigenesis and (3) complete a structural comparison of the Pim to other protein kinases, and (4) suggest potential lead compounds for drug discovery and develop peptidomimetics. The results obtained in this proposal will provide the necessary impetus to target drug discovery towards finding inhibitors of Pim activity. We will define which tumors over-express Pim, the biologic activity of this protein kinase, and develop a structural model for its function. Because other protein kinases have been successfully targeted and drugs are now in the clinic, it is highly likely that inhibitors of this protein kinase could be developed.

该提案的目标是验证蛋白激酶Pim-1是化疗开发的潜在靶点的假设。Pim-1蛋白激酶被克隆作为一个逆转录病毒插入点，在一个屏幕上的基因，增强肿瘤的c-myc。携带这种蛋白质的转基因小鼠T细胞淋巴瘤的发病率升高，并且这些小鼠对致癌物治疗极其敏感，这进一步表明Pim在肿瘤发生中是重要的.我们的研究结果表明，Pim-1蛋白激酶是一种核酶，调节bcl-2 mRNA和mdm 2蛋白的水平，表明Pim-1可能影响p53的功能。本提案的目的是：（1）确定Pim活性是否在各种肿瘤类型中升高，（2）检查Pim是否调节肿瘤发生所需的特定途径，（3）完成Pim与其他蛋白激酶的结构比较，以及（4）为药物发现和开发肽模拟物提供潜在的先导化合物。在这项建议中获得的结果将提供必要的动力，以靶向药物发现对寻找Pim活性的抑制剂。我们将确定哪些肿瘤过度表达Pim，这种蛋白激酶的生物活性，并开发其功能的结构模型。由于其他蛋白激酶已被成功靶向，并且药物现已进入临床，因此很有可能开发出这种蛋白激酶的抑制剂。