Identification of inhibitors for the Rsk2 protein kinase

Rsk2 蛋白激酶抑制剂的鉴定

• 批准号: 6465982
• 负责人: Deborah Lannigan
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-08 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6465982
• 关键词: X ray crystallography; affinity chromatography; antigen antibody reaction; binding sites; biotherapeutic agent; chemical registry /resource; drug discovery /isolation; drug screening /evaluation; enzyme activity; enzyme inhibitors; enzyme structure; enzyme substrate complex; high throughput technology; isozymes; peptide chemical synthesis; pharmacokinetics; phosphorylation; protein engineering; protein kinase; recombinant proteins; ribosomal proteins; technology /technique development

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.

描述（由申请人提供）： 丝裂原激活蛋白激酶 (MAPK) 通路的组成部分是 已知过度表达或含有激活突变具有致癌性，并且 发生在许多人类肿瘤中，如头颈、结肠和乳腺癌 癌症。由于其在肿瘤发生中的重要性，许多药物被发现 努力针对 MAPK 途径的各个组成部分，其中一些 抑制剂正在进行临床试验。然而，目前还没有已知的抑制剂 pp90-kDa 核糖体 S6 Ser/Thr 蛋白激酶 (Rsk) 家族，它们是 MAPK 的重要下游效应子。 Rsk 的组成型活性突变体 已经证明 Rsk 在细胞增殖和 生存并可能参与乳腺癌的发生和/或进展。 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将 Rsk 开发为药物靶点 发现。一种新型体外 Rsk 活性测定方法，适用于高 将开发通量筛选（HTS）。该 HTS 测定将用于 筛选 NIH 多样性和机制集。抑制剂的特异性 从屏幕获得的信息将使用辅助屏幕进行验证。这些 研究将确定用于进一步药物发现的“先导化合物”。 此外，为了促进药物发现，Rsk 的结构研究 没有抑制剂结合将进行长期目标是获得 3D结构。