PROJECT SUMMARY The objective is to discover selective CNS penetrant inhibitors of the kinase responsible for phosphorylation of OLIG2 and a potential target for treatment of glioblastoma. In this proposal, Curtana Pharmaceuticals Inc. will discover new kinase inhibitors based on findings that prototypical compounds inhibit OLIG2 phosphorylation and the degree of inhibition is dependent on key aspects of compound structure. A medicinal chemistry plan is proposed to identify new compounds with improved properties. These compounds will be assessed for kinase inhibition and then screened for metabolic stability. Stable compounds will be assessed in vivo for CNS penetration. The inhibitor with the best profile will be tested further in a preliminary efficacy model for efficacy in tumor reduction of human-derived glioblastoma tumors grafted into mouse flank to prove feasibility for the approach. This inhibitor will be tested for drug interaction risk to validate the inhibitor for further development or to identify risks requiring lead optimization.