%0 Journal Article
%A Milgram, Benjamin C.
%A Borrelli, Deanna R.
%A Brooijmans, Natasja
%A Henderson, Jack A.
%A Hilbert, Brendan J.
%A Huff, Michael R.
%A Ito, Takahiro
%A Jackson, Erica L.
%A Jonsson, Philip
%A Ladd, Brendon
%A O’Hearn, Erin L.
%A Pagliarini, Raymond A.
%A Roberts, Simon A.
%A Ronseaux, Sébastien
%A Stuart, Darrin D.
%A Wang, Weixue
%A Guzman-Perez, Angel
%T 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
%J Journal of medicinal chemistry
%V 68
%N 3
%@ 0095-9065
%C Washington, DC
%I ACS
%M PUBDB-2025-04149
%P 2403 - 2421
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39824516
%R 10.1021/acs.jmedchem.4c02377
%U https://bib-pubdb1.desy.de/record/638682