Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR -Mutated Non-Small Cell Lung Cancer

Molecular Cancer Therapeutics
Toshiyuki HiranoTomoko Betsuyaku

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...Continue Reading

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Citations

Dec 19, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Misako NagasakaSai-Hong Ignatius Ou
Dec 23, 2019·Leukemia Research·Hiroaki TanakaMasahiro Takeuchi
Jul 29, 2021·ELife·Ioannis GaldadasFrancesco Luigi Gervasio
Aug 16, 2019·Journal of Medicinal Chemistry·Janina NiggenaberDaniel Rauh

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