9FRD

Wildtype EGFR bound with Compound 23

This is a non-PDB format compatible entry.

Summary for 9FRD

• Entry DOI: 10.2210/pdb9frd/pdb
• Descriptor: Epidermal growth factor receptor, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, (7~{S})-3-[(3-chloranyl-2-methoxy-phenyl)amino]-2-(3-fluoranylpyridin-4-yl)-7-(2-methoxyethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one, ... (5 entities in total)
• Functional Keywords: kinase, egfr wildtype, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38214.05

Authors

Pagliarini, A.R.,Milgram, B.C.,Borrelli, D.R.,OHearn, E.,Huff, M.R.,Ladd, B.,Brooijmans, N.,Henderson, J.A.,Hilbert, B.J.,Wang, W.,Ito, T. (deposition date: 2024-06-18, release date: 2025-01-29, Last modification date: 2025-02-26)

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., 68:2403-2421, 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 (2.06 Å)