As the first essential step toward a novel therapy for GBM, the goal of this proposed project was to discover compounds that specifically inhibit functions of Crk and CrkL. High throughput screening of chemical libraries and validation of hit compounds required close collaboration with the University of Kansas High Throughput Screening Laboratory (KU-HTSL), which provided technical expertise, instrumentation, and personnel for optimization of the fluorescence polarization-based binding assay, high throughput screening, and biochemical validation. Fluorescence polarization assays for screening system establishment, library screening, and the initial biochemical validation were conducted in the KU-HTSL. Molecular cloning, protein purification, and cell-based validations were carried out at Children’s Mercy. We identified several lead compounds for drug development and evaluated the lead compounds using cell-based and biochemical assays.