Design, synthesis and biological evaluation of selective inhibitors against the L858R/T790 M/C797S mutant EGFR kinase based on the scaffold of brigatinib.

Based on the scaffold of brigatinib, we designed and synthesized a series of novel EGFR tyrosine kinase inhibitors, followed by the evaluation of their activity against the L858R/T790 M/C797S mutant EGFR kinase. Compound 8c showed significantly higher inhibitory activity (IC50 = 0.48 nM) than brigatinib (IC50 = 3.41 nM), and preferred to inhibit the L858R/T790 M/C797S mutant EGFR kinase rather than other subtypes and ALK. In the proliferation inhibition assays, compound 8c also exhibited significantly greater potency (IC50 = 0.249 μM) and selectivity against BaF3-EGFR(L858R/T790 M/C797S) cell line compared to brigatinib (IC50 = 0.751 μM). Furthermore, cell cycle arrest assay, apoptosis induction assays, Western blot assay, colony formation inhibition assay, cell migration inhibition assays, tube formation assay, and docking analysis were carried out to study the action mechanism of compound 8c. All these results indicated that compound 8c has the potential for further evaluation of in vivo efficacy and druggability.