9DM8

EGFR wildtype in complex with BI-8128

This is a non-PDB format compatible entry.

Summary for 9DM8

• Entry DOI: 10.2210/pdb9dm8/pdb
• Descriptor: Epidermal growth factor receptor, (6M)-1-{2-[4-(2-methoxyethyl)piperazin-1-yl]-1-methyl-4-[(1S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1H-imidazo[4,5-c]pyridin-6-yl}-6-(4-methoxypyridin-3-yl)-4-methyl-1H-pyrazolo[4,3-c]pyridine, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: kinase, drug discovery, cancer, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38110.08

Authors

Heppner, D.E.,Damghani, T.,Lin, K.S. (deposition date: 2024-09-12, release date: 2026-01-28, Last modification date: 2026-02-25)

Primary citation

Damghani, T.,Song, S.,Lin, K.S.,Li, J.,Heppner, D.E.
Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.
Acs Med.Chem.Lett., 2026

PubMed Abstract: Inhibitors targeting mutant EGFR remain a persistent need in combating drug resistance in non-small cell lung cancer. To better understand the molecular factors involved in targeting T790M and C797S mutations, we determined X-ray cocrystal structures of fourth-generation inhibitors BI-8128 and BI-4732. Analysis from molecular dynamics and thermodynamic integration calculations correlated with biochemical and cellular measurements indicate that BI-8128 binds the double T790M/C797S more strongly than the single mutations individually. This observation showcases strengths in the design of these fourth-generation EGFR inhibitors as profile criteria require drugs to inhibit an array of oncogenic and drug resistance mutations.

PubMed: 41684669
DOI: 10.1021/acsmedchemlett.5c00725

Experimental method

X-RAY DIFFRACTION (2.13 Å)