Design, synthesis and biological evaluation of novel osimertinib derivatives as reversible EGFR kinase inhibitors

A series of osimertinib derivatives without acrylamide groups were synthesized and their inhibitory rates against L858R/T790M/C797S mutated EGFR kinase and antiproliferation activities against non-small cell lung cancer cell lines (A549, H1975) were evaluated. The preferred compounds were selected and their in vitro inhibitory activities against various EGFR kinases (wild-type, L858R/T790M, L858R/T790M/C797S) and c-Met kinase were tested. Compound 9h showed remarkable inhibitory activity against the wild type (IC50 = 29 nM), L858R/ T790M mutant type (IC50 = 10 nM) and L858R/T790M/C797S mutant type (IC50 = 242 nM) as reversible EGFR kinase inhibitor, which was selected to further perform the AO/EB staining assays, cell cycle distribution assays and wound-healing assays on A549 and/or H1975 cell lines. The results showed dose-dependent activities of the induction of cell apoptosis, G1/G0-phase arrestation and inhibition of migration. Compound 22a showed remarkable inhibitory activity against the L858R/T790M/C797S mutant EGFR kinase (IC50 = 137 nM), which was nearly three times compared to osimertinib (IC50 = 410 nM). It's worth noting that 22a exhibited excellent kinase selectivity against the L858R/T790M/C797S mutant EGFR kinase rather than the wild-type, which reached 5.4 times and far more than the 0.012 times of osimertinib. Additionally, molecular docking analyses were performed to explain the action modes between the compounds and the corresponding EGFR kinases. In conclusion, compounds 9h and 22a have been demonstrated as promising candidates and worth further study.

Automated summary

A series of osimertinib derivatives were synthesized and evaluated for their inhibitory activities against mutant EGFR kinases. Compound 9h showed significant inhibitory activity against various EGFR kinases, while compound 22a exhibited excellent selectivity against the L858R/T790M/C797S mutant EGFR kinase.