Structural Insights into Brain-Penetrant EGFR Tyrosine Kinase Inhibitors with Enhanced Potency

Abstract An increasing focus on neurological diseases has led to a desire to enhance kinase inhibitor exposure within the central nervous system (CNS). In an effort to replicate their success in lung cancer, tyrosine kinase inhibitors (TKIs) targeting EGFR have been redesigned for enhanced blood-brain barrier (BBB) penetration, with several reaching clinical trials. To better understand the structural and functional attributes of these BBB-penetrating TKIs, we carried out X-ray crystallographic experiments and potency measurements. Our results show that structural alterations aimed at rationally enhancing CNS exposure result in diverse interactions with various regions of the EGFR kinase domains. Both biochemical and cellular potency are improved by these new moieties designed to enhance BBB penetration, with the most effective being those that introduce salt bridges with EGFR when combined with certain halogen substitutions. This work provides a rational framework for achieving a “two-for-one” benefit to drug profile, in which optimization of CNS exposure and target binding can be accomplished together.