Dacomitinib: another option for EGFR-mutant lung cancer?

Mitsudomi, Tetsuya

doi:10.1016/s1470-2045(14)70487-5

Cited by 7 publications

(1 citation statement)

References 4 publications

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“…As a result, the binding of these inhibitors is sterically blocked by the bulky methionine moiety, which disrupts water-mediated hydrogen bond formation between the inhibitors and the T790M of EGFR [ 4 , 12 ]. In this respect, second-generation inhibitors (afatinib and dacomitinib) have been developed to overcome the resistance associated with the T790M mutation ( Figure 1 ) [ 14 , 15 ]. However, they have poor kinase selectivity between EGFR T790M mutants and the wild type (WT) EGFR.…”

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confidence: 99%

Design and Synthesis of New Hydantoin Acetanilide Derivatives as Anti-NSCLC Targeting EGFRL858R/T790M Mutations

et al. 2022

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Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFRL858R/T790M inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which 5a and 5f were the most potent. Compounds 5a and 5f possessed potent anticancer activity on H1975 cells with IC50 values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, 5a and 5f showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of 5a. Besides, active hydantoin derivative 5a strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that 5a could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy.

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