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Identification, Development, and Evaluation of Brain-Penetrant Small-Molecule Inhibitors of Epidermal Growth Factor Receptor in Glioblastoma


The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma (GBM) tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure has been attributed to the inability of clinically tested EGFR TKIs (e.g. erlotinib, gefitinib, lapatinib, afatinib) to effectively penetrate the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit the oncogenic forms of EGFR that drive GBM to induce a tumor response. Hence, there is a highly unmet medical need for effective therapeutics for GBM. In these studies, we detail the identification, development, and evaluation of brain-penetrant, small molecule inhibitors of EGFR to a clinical compound. This dissertation begins with a structure-activity relationship (SAR) to develop JCN037 as an early pre-clinical lead molecule. JCN037 was developed from a 4-anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area, and by introduction of an ortho-fluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model. However, JCN037 was limited by a poor in vivo half life and a quick metabolism. Further SAR analysis lead to the development of JCN068, an EGFR TKI that potently inhibits oncogenic forms of EGFR with improved BBB penetration (>3:1 brain-to-plasma ratio). Compared to clinically tested EGFR TKIs, JCN068 demonstrates improved potency activity against EGFR amplified/mutant patient-derived cell cultures, significantly higher BBB, ideal clinical candidate in vivo pharmacology, and superior efficacy in multiple EGFR-driven orthotopic glioblastoma xenograft models. Additionally, rapid changes in tumor 18F-fluorodeoxyglucose (18F-FDG) uptake using non-invasive positron emission tomography (PET) was utilized as an effective predictive biomarker of response to JCN068 therapy in vivo. JCN068 is currently advancing in IND-enabling studies as a new potential therapeutic for EGFR-driven GBM.

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