Design, synthesis and biological evaluation of novel tumor hypoxia-activated EGFR tyrosine kinase inhibitors

Abstract

Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (IC₅₀ = 23 nM) against EGFR^L858R/T790M and displayed about 21-fold inhibitory activity decrease against EGFR^wt. Under hypoxia, JT21 exhibited more significant proliferation inhibitory activities against H1975 cells (IC₅₀ = 7.39 ± 2.20 nM) and HCC827 cells (IC₅₀ = 5.88 ± 0.85 nM) than that of AZD9291, which was about 5 times more effective than normoxia activities. Meanwhile, the weak inhibition effects on A549 and BEAS-2B cells suggested JT21 might be a selective inhibitor for EGFR mutations with low toxicity. Furthermore, JT21 could induce apoptosis of H1975 cells under hypoxia and showed good bio-reductive property.

Keywords: AZD9291; EGFR inhibitors; Hypoxia-activated; L858R/T790M and del19 mutants; Selective.