Structural Insights into the Potency of Brain-Penetrant EGFR Inhibitors

An increasing focus on kinase targeting in neurological diseases has led to improvements in drug exposure within the central nervous system (CNS). Tyrosine kinase inhibitors (TKIs) targeting EGFR have gradually evolved to exhibit enhanced CNS exposure through rational design relevant to several cancers including glioblastoma with many currently in clinical testing. To better appreciate the structural and functional attributes of these blood-brain-barrier (BBB)-penetrant TKIs containing certain functional groups for optimal BBB-penetrance, we carried out X-ray crystallographic and potency measurements. Our results showcase how functional groups incorporated within TKI scaffolds to improve BBB exposure can also enhance EGFR potency, as observed for AZD3759. The results of this work will aid in the design of superiorly effective TKIs with critical on-target potency profiles toward addressing kinases in CNS diseases.