PDBsum entry 5y9t

Transferase

PDB id: 5y9t

Contents

Protein chain

300 a.a.

Ligands

8RC

References listed in PDB file

Key reference

• Title: Pharmacological and structural characterizations of naquotinib, A novel third-Generation egfr tyrosine kinase inhibitor, In egfr-Mutated non-Small cell lung cancer.
• Authors: T.Hirano, H.Yasuda, J.Hamamoto, S.Nukaga, K.Masuzawa, I.Kawada, K.Naoki, T.Niimi, S.Mimasu, H.Sakagami, K.Soejima, T.Betsuyaku.
• Ref.: Mol Cancer Ther, 2018, 17, 740-750. [DOI no: 10.1158/1535-7163.MCT-17-1033]
• PubMed id: 29467275

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 EGFR 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 EGFR 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 EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations and help clarify the biology of EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(4); 740-50. ©2018 AACR.