5Y9T

Crystal Structure of EGFR T790M mutant in complex with naquotinib

Summary for 5Y9T

• Entry DOI: 10.2210/pdb5y9t/pdb
• Descriptor: Epidermal growth factor receptor, 6-ethyl-3-[[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]oxy-pyrazin e-2-carboxamide (2 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38468.55

Authors

Mimasu, S.,Tomimoto, Y.,Maiko, I.,Yasushi, A.,Tatsuya, N. (deposition date: 2017-08-28, release date: 2018-07-11, Last modification date: 2024-10-30)

Primary citation

Hirano, T.,Yasuda, H.,Hamamoto, J.,Nukaga, S.,Masuzawa, K.,Kawada, I.,Naoki, K.,Niimi, T.,Mimasu, S.,Sakagami, H.,Soejima, K.,Betsuyaku, T.
Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, inEGFR-Mutated Non-Small Cell Lung Cancer.
Mol. Cancer Ther., 17:740-750, 2018

PubMed Abstract: Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion and exon 19 deletion+T790M was comparable with that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using and structural analyses and suggested the mechanism of activation and resistance to EGFR-TKIs of exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with mutations and help clarify the biology of exon 20 insertion mutations. .

PubMed: 29467275
DOI: 10.1158/1535-7163.MCT-17-1033

Experimental method

X-RAY DIFFRACTION (3.25 Å)