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）途径的组分， 过表达或含有激活突变的基因已知是致癌的， 发生在许多人类肿瘤中，如头颈部、结肠和乳腺 癌由于其在肿瘤发生中的重要性，许多药物发现 已经针对MAPK途径的各种组分进行了努力， 抑制剂正在进行临床试验。然而，没有已知的抑制剂， pp 90-kDa核糖体S6 Ser/Thr蛋白激酶（Rsk）家族， MAPK的重要下游效应物。Rsk组成型活性突变体 已经证明Rsk在细胞增殖中起重要作用， 存活，并可能参与乳腺癌的发生和/或进展。 因此，Rsk是一个重要的，新的抗癌治疗靶点。 该项目的总体目标是将Rsk开发为药物治疗的靶点。 的发现一种新的体外Rsk活性测定法，适用于高 将开发通量筛选（HTS）。该HTS检测试剂盒将用于 筛选NIH多样性和机制集。抑制剂的特异性 将使用二级屏幕验证从屏幕获得的信息。这些 研究将确定“先导化合物”，以进一步发现药物。 此外，为了促进药物发现，Rsk与 将进行无抑制剂结合的研究，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.