6LUD

Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib

Summary for 6LUD

• Entry DOI: 10.2210/pdb6lud/pdb
• Descriptor: Epidermal growth factor receptor, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide (3 entities in total)
• Functional Keywords: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37831.76

Authors

Kawauchi, H.,Fukami, T.A.,Sato, S.,Endo, M.,Torizawa, T.,Kashima, K.,Chiba, T.,Sakamoto, H. (deposition date: 2020-01-27, release date: 2020-10-07, Last modification date: 2023-11-29)

Primary citation

Kashima, K.,Kawauchi, H.,Tanimura, H.,Tachibana, Y.,Chiba, T.,Torizawa, T.,Sakamoto, H.
CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation.
Mol.Cancer Ther., 19:2288-2297, 2020

PubMed Abstract: Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S and In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type. Furthermore, crystal structure analysis suggested that CH7233163 is a noncovalent ATP-competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib-resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

PubMed: 32943545
DOI: 10.1158/1535-7163.MCT-20-0229

Experimental method

X-RAY DIFFRACTION (2.05 Å)