Identification of inhibitors for the Rsk2 protein kinase

描述(由申请人提供)： 丝裂原活化蛋白激酶(MAPK)途径的组成部分是 已知过度表达或包含激活突变是致癌和 发生在许多人类肿瘤中，如头和颈部、结肠和乳房 癌症。由于它在肿瘤发生中的重要性，许多药物的发现 已经针对MAPK途径的各种组件以及其中的一些组件进行了努力 抑制剂正在进行临床试验。然而，目前还没有已知的抑制药物 Pp90-kDa核糖体S6丝氨酸/苏氨酸蛋白激酶(RSK)家族，它们是 MAPK的重要下游效应因子。RSK基因的结构性活性突变体 已经证明RSK在细胞增殖和修复中发挥重要作用。 并且可能与乳腺癌的发生和/或进展有关。 因此，RSK是抗癌治疗的一个重要的新靶点。 该项目的总体目标是开发RSK作为药物靶标 发现号。一种新的体外测定RSK活性的方法 将开发吞吐量筛选(HTS)技术。这项HTS测试将用于 筛选NIH多样性和机械组。抑制剂的特异性 从屏幕上获得的数据将使用二级屏幕进行验证。这些 研究将为进一步的药物发现确定“先导化合物”。 此外，为了促进药物发现，与和的RSK结构研究 在没有抑制剂的情况下，将进行绑定，长期目标是获得 3D结构。

DESCRIPTION (provided by applicant): Components of the mitogen activated protein kinase (MAPK) pathway that are overexpressed or contain activating mutations are known to be oncogenic and occur in a number of human tumors such as head and neck, colon and breast cancer. Because of its importance in oncogenesis numerous drug discovery efforts have targeted various components of the MAPK pathway and some of these inhibitors are in clinical trials. However, there are no known inhibitors of the pp90-kDa ribosomal S6 Ser/Thr protein kinase (Rsk) family, which are important downstream effectors of MAPK. Constitutively active mutants of Rsk have demonstrated that Rsk plays important roles in cell proliferation and survival and may be involved in breast cancer initiation and/or progression. Thus Rsk is an important, novel target for anti-cancer therapy. The overall goals of this project are to develop Rsk as a target for drug discovery. A novel, in vitro, assay for Rsk activity suitable for high throughput screening (HTS) will be developed. This HTS assay will be used to screen the NIH Diversity and Mechanistic Sets. The specificity of inhibitors obtained from the screens will be verified using secondary screens. These studies will identify "lead compounds" for further drug discovery. Additionally, to facilitate drug discovery, structural studies of Rsk with and without inhibitor bound will be performed with the long term goal of obtaining the 3D structure.