Identification of inhibitors for the Rsk2 protein kinase

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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.