Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 183, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111709
Keywords
Non-small cell lung cancer (NSCLC); L858R/T790M double mutant; Apoptosis; Pharmacokinetic properties; Anti-Tumor activity
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Funding
- Natural Science Foundation of Guangdong Province, China [2018A030313539]
- youth innovation project of Guangzhou university of Chinese Medicine, China [2017KQNCX033]
- Science Foundation of Guangdong Provincial Hospital of Chinese Medicine, China [2017KT1525]
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A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-41 exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (-)-41 induced cell apoptosis and reduced phosphorylation of EGFR and AKT in a dose-dependent manner. Furthermore, (-)-41 exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUCO-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t(1/2) = 1.12 h) of (-)-41 displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (-)-41 in vivo resulted in a significant reduction of the tumor volume (TGI: 9430%). Altogether, these results suggest that (-)-41 warrants further investigation in Non-Small cell lung cancer (NSCLC) therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.
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