2. Academic Validation
  3. 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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157229
    98.25%, EGFR Inhibitor