9FQS

EGFR Exon20 insertion mutant NPG bound with Compound 39

This is a non-PDB format compatible entry.

Summary for 9FQS

• Entry DOI: 10.2210/pdb9fqs/pdb
• Descriptor: Epidermal growth factor receptor, 1,2-ETHANEDIOL, 3-[(3-fluoranyl-2-methoxy-phenyl)amino]-2-[3-[2-[(2R)-1-propanoylpyrrolidin-2-yl]ethynyl]pyridin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39303.30

Authors

Hilbert, B.J.,Brooijmans, N.,Milgram, B.C.,Pagliarini, R.A. (deposition date: 2024-06-17, release date: 2025-01-29)

Primary citation

Milgram, B.C.,Borrelli, D.R.,Brooijmans, N.,Henderson, J.A.,Hilbert, B.J.,Huff, M.R.,Ito, T.,Jackson, E.L.,Jonsson, P.,Ladd, B.,O'Hearn, E.L.,Pagliarini, R.A.,Roberts, S.A.,Ronseaux, S.,Stuart, D.D.,Wang, W.,Guzman-Perez, A.
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

PubMed 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 () 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.

PubMed: 39824516
DOI: 10.1021/acs.jmedchem.4c02377

Experimental method

X-RAY DIFFRACTION (1.783 Å)