9N6G

EGFR(T790M/V948R) in complex with LN2827

This is a non-PDB format compatible entry.

Summary for 9N6G

• Entry DOI: 10.2210/pdb9n6g/pdb
• Descriptor: Epidermal growth factor receptor, N-{(3P)-3-[(4P)-5-(2-acetamidopyridin-4-yl)-2-(methylsulfanyl)-1H-imidazol-4-yl]phenyl}-2,6-difluorobenzamide (3 entities in total)
• Functional Keywords: inhibitors, cancer therapy, drug design, transferase
• Biological source: Spodoptera frugiperda
• Total number of polymer chains: 4
• Total formula weight: 150213.87

Authors

Chitnis, S.P.,Hartman, T.J.,Heppner, D.E. (deposition date: 2025-02-05, release date: 2025-08-13)

Primary citation

Chitnis, S.P.,Wittlinger, F.,Mollers, M.,Hartman, T.J.,Gunther, M.,Eck, M.J.,Laufer, S.A.,Heppner, D.E.
Structure-Activity Relationships of Inactive-Conformation Binding EGFR Inhibitors: Linking the ATP and Allosteric Pockets.
Arch Pharm, 358:e70027-e70027, 2025

PubMed Abstract: The epidermal growth factor receptor (EGFR) tyrosine kinase is an important therapeutic target in non-small cell lung cancer (NSCLC). However, the continual emergence of resistance mutations in the treatment of EGFR mutation-positive NSCLC with currently approved tyrosine kinase inhibitors warrants the development of next-generation inhibitors. Since research for ATP-competitive EGFR tyrosine kinase inhibitors (TKIs) that extend into the back pocket has been neglected in the recent past, we survey the extent to which such binding functional groups can be incorporated into an ATP-site imidazole scaffold. We find that meta-substituted amide linkers derivatized with fluorine in 2,6-positions and/or a hydroxy group in 3-position of the back pocket phenyl exhibit the highest potency. Structural insights into how the back pocket groups are bound through points of connection provide new directions for the discovery and optimization of inactive conformation targeting agents in EGFR and other kinases.

PubMed: 40665765
DOI: 10.1002/ardp.70027

Experimental method

X-RAY DIFFRACTION (2.59 Å)