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 Med Chem. 2025 Feb 13;68(3):2403-2421. doi: 10.1021/acs.jmedchem.4c02377.
Benjamin C Milgram  1 ,  Deanna R Borrelli  1 ,  Natasja Brooijmans  1 ,  Jack A Henderson  1 ,  Brendan J Hilbert  1 ,  Michael R Huff  1 ,  Takahiro Ito  1 ,  Erica L Jackson  2 ,  Philip Jonsson  1 ,  Brendon Ladd  1 ,  Erin L O'Hearn  1 ,  Raymond A Pagliarini  1 ,  Simon A Roberts  1 ,  Sébastien Ronseaux  1 ,  Darrin D Stuart  1 ,  Weixue Wang  1 ,  Angel Guzman-Perez  1
Affiliations
  • 1. Scorpion Therapeutics, 1 Winthrop Square, Boston, Massachusetts 02110, United States.
  • 2. Scorpion Therapeutics, South San Francisco, California 94080, United States.
PMID: 39824516 DOI: 10.1021/acs.jmedchem.4c02377
Abstract

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.

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