Pim 1 protein kinase as a target for drug discovery

这项建议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蛋白激酶被克隆为一个逆转录病毒插入点，用于筛选通过c-myc增强肿瘤形成的基因。携带这种蛋白的转基因小鼠患T细胞淋巴瘤的几率较高，而且这些小鼠对致癌物治疗极其敏感，这进一步表明Pim在肿瘤发生中具有重要作用。我们的结果表明，Pim-1蛋白激酶是一种核酶，它调节bcl2mRNA和MDM2蛋白的水平，提示Pim-1可能影响P53的功能。这项建议的目的是：(1)确定PIM活性是否在不同类型的肿瘤中升高，(2)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)建议潜在的先导化合物用于药物开发和肽仿制。这项建议的结果将为寻找PIM活性抑制剂的靶向药物发现提供必要的动力。我们将定义哪些肿瘤过度表达Pim，这种蛋白激酶的生物学活性，并开发其功能的结构模型。由于其他蛋白激酶已经成功地被靶向，药物现在已经进入临床，这种蛋白激酶的抑制剂很有可能被开发出来。

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.