Optimization of Potent, Efficacious, Selective and Blood–Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations

Herein, we report the optimization
of a series of epidermal growth
factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using
structure-based drug design (SBDD), leading to the discovery of compound 28, a potent and wild type selective molecule, which demonstrates
efficacy in multiple EGFR Ex20Ins xenograft models and blood–brain
barrier penetration in preclinical species. Building on our earlier
discovery of an in vivo probe, SBDD was used to design
a novel bicyclic core with a lower molecular weight to facilitate
blood–brain barrier penetration. Further optimization including
strategic linker replacement and diversification of the ring system
interacting with the c-helix enabled photolytic and metabolic stability
improvements. Together with refinement of molecular properties important
for achieving high brain exposure, including molecular weight, H-bonding,
and polarity, 28 was identified.