The long-term objective of this proposal is to apply TetheringSM fragment-based drug discovery to obtain novel therapeutics for the treatment of cancer.  Conformation-specific inhibitors of the kinase MEK1 provide a new class of cancer therapeutics that broadly target cancer cells at the molecular level yet are not generally cytotoxic.  TetheringSM allows a greater survey of chemical diversity space than is achievable using the large compound libraries typically screened by pharmaceutical firms.  TetheringSM with extenders, a variation of this approach, was used to identify high potency MEK1 inhibitors (IC50's < 0.3 microM) during Phase I. TetheringSM with extenders is particularly powerful for target classes like kinases that contain an active site that is highly conserved in one region yet significantly divergent in adjacent regions.  Moreover_ this approach provides not only an efficient means of ligand discovery but also a direct path to lead optimization since the target protein is used as a template for the construction of its own inhibitor.  This Phase II proposal proposes to carry forward the potent MEKI inhibitors identified in Phase I starting with 2-3 chemically distinct early lead series and ending with a clinical candidate compound for IND enabling studies.