7ZYM

Crystal Structure of EGFR-T790M/C797S in Complex with Brigatinib

Summary for 7ZYM

• Entry DOI: 10.2210/pdb7zym/pdb
• Descriptor: Epidermal growth factor receptor, 5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (3 entities in total)
• Functional Keywords: egfr, t790m/c797s, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38299.70

Authors

Niggenaber, J.,Kleinboelting, S.,Mueller, M.P.,Rauh, D. (deposition date: 2022-05-25, release date: 2023-05-03, Last modification date: 2024-02-07)

Primary citation

Grabe, T.,Jeyakumar, K.,Niggenaber, J.,Schulz, T.,Koska, S.,Kleinbolting, S.,Beck, M.E.,Muller, M.P.,Rauh, D.
Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.
Acs Med.Chem.Lett., 14:591-598, 2023

PubMed Abstract: Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.

PubMed: 37197473
DOI: 10.1021/acsmedchemlett.2c00514

Experimental method

X-RAY DIFFRACTION (2.5 Å)