Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer

After L858R and ex19del epidermal growth factor receptor
(EGFR)
mutations, ex20ins mutations are the third most common class of driver-mutations
in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-,
and third-generation EGFR tyrosine kinase inhibitors (TKIs) are generally
ineffective for ex20ins patients due to insufficient mutant activity
and selectivity over wild-type EGFR, leading to dose-limiting toxicities.
While significant advances in recent years have been made toward identifying
potent EGFR ex20ins mutant inhibitors, mutant vs wild-type EGFR selectivity
remains a significant challenge. STX-721 (53) is a potent,
irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants
and demonstrates excellent mutant vs wild-type selectivity both in
vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials
for EGFR/HER2 ex20ins-driven NSCLC.