Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors

  • Bioorg Med Chem. 2017 Sep 1;25(17):4553-4559. doi: 10.1016/j.bmc.2017.06.004.
Hongying Gao  1 ,  Zimo Yang  2 ,  Xinglin Yang  2 ,  Yu Rao  3
Affiliations
  • 1. Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100084, PR China; MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, PR China.
  • 2. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China.
  • 3. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China. Electronic address: [email protected].
PMID: 28716641 DOI: 10.1016/j.bmc.2017.06.004
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 of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, 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.

Keywords
Epidermal growth factor receptor-tyrosine kinase inhibitors; Fluoride; N-Oxide metabolites; Non-small cell lung cancer; Osimertinib.