Research Project
6072538
The Rho-family of small G-proteins are key regulators of the eukaryotic actin cytoskeleton and thus mediate many of the physiological processes involving cell motility. Such processes include the immune response (6,7), neuronal and embryonic development (8-11), as well as cell-cell and cell- extracellular matrix interactions (12-14). It has also become apparent that Rho-mediated signal transduction pathways are essential to many aspects of gene transcription and cell division (15-18). Besides their obvious importance to normal cellular events, Rho-family pathways are also highly relevant in many disease states. These include Ras-mediated malignancies (19), metastatic invasion (20), bacterial and viral infections (21,22,23), hypertension (2,24), immunosupression (6) and developmental defects (26). The ability to target these pathways in a disease specific manner would be of clear benefit to medical science. In this regard, there is a large body of evidence suggesting that the Guanine Nucleotide Exchange Factors (GEFs) play a significant role in determining Rho pathway Specificity (30-33). This has made these upstream activators of Rho-proteins highly attractive targets for therapeutic intervention. Accordingly, it is the principle aim of this Phase I proposal to adapt a novel, low throughput assay that has been developed at Cytoskeleton Inc. into a robust, cost effective KTS assay for the purpose of identifying small molecule compounds that can inhibit GEF activity. We also anticipate that the assay will be useful in screening for novel GEF proteins. If successful, our Phase II proposal will focus on screening compound libraries for GEF inhibitory compounds. We believe that such compounds will be of use as tools for basic research and for the purpose of therapeutic intervention in a potentially wide range of human diseases. PROPOSED COMMERCIAL APPLICATIONS: Our market research has determined that there is a wide interest in HTS GEF inhibition assays. We estimate that there is a multimillion dollar market for the sale of these screens. Clearly, any drug leads that result from a successful Phase II will be of a potentially large monetary and social value.
