期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 38, 期 1, 页码 -出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2023.2205605
关键词
NSCLC; EGFR mutations; EGFR(L858R/T790M); antitumor; derivatives
In this study, two series of EGFR kinase inhibitors were designed and synthesised. Compound B1 showed selective inhibition against EGFR (L858R/T790M) with an IC50 value of 13 nM and a 76-fold selectivity for EGFR (WT). In vitro experiments demonstrated that compound B1 effectively inhibited proliferation of H1975 cells with an IC50 value of 0.087 μM. Mechanistic studies confirmed the selective inhibition of EGFR (L858R/T790M) by compound B1 through cell migration and apoptosis assays.
EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as classical mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFR(L858R/T790M) and more than 76-fold selectivity for EGFR(WT). Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 mu M. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFR(L858R/T790M) by cell migration assay and apoptosis assay.
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