Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors. Issue 17 (1st September 2017)

• Record Type: Journal Article
• Authors: Gao, Hongying; Yang, Zimo; Yang, Xinglin; Rao, Yu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 17(2017)
• Page Start: 4553
• Page End: 4559
• Publication Date: 2017-09-01
• Subjects: Osimertinib -- N-Oxide metabolites -- Fluoride -- Non-small cell lung cancer -- Epidermal growth factor receptor-tyrosine kinase inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.06.004
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N -oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of1 –6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound2, the newly synthesized N -oxide metabolite in N, N, N ′-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.