DDIS-08. DEVELOPMENT OF BRAIN-PENETRANT EGFR INHIBITORS FOR GLIOBLASTOMA

Abstract The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for GBM patients. This can be attributed to the inability of conventional EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. For example, less than 10% of plasma drug concentrations are achieved in the brain for all FDA approved EGFR TKIs. Herein, we performed a structure-activity relationship (SAR) from the 4-anilinoquinazoline scaffold to improve brain penetrance by modifications of physiochemical properties amenable to BBB penetration. Our synthesis scheme aimed to develop EGFR TKIs with low molecular weight and polar surface area, few rotatable bonds and hydrogen bond donors and acceptors, while having high lipophilicity. This yielded novel EGFR TKIs with nanomolar potency against EGFR mutant, GBM patient-derived cells in culture, high BBB penetration (200% brain to plasma), and efficacy against patient-derived orthotopic GBM xenografts. Current efforts are aimed at improving metabolic stability and bioavailability to obtain a clinical EGFR TKI drug candidate for the treatment of GBM.