Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors

Hongying Gao; Zimo Yang; Xinglin Yang; Yu Rao

doi:10.1016/j.bmc.2017.06.004

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. Epub 2017 Jul 8.

Authors

Hongying Gao¹, Zimo Yang², Xinglin Yang², Yu Rao³

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: yrao@tsinghua.edu.cn.

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.

MeSH terms

Acrylamides / chemical synthesis*
Acrylamides / pharmacology
Acrylamides / therapeutic use
Aniline Compounds
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Female
Humans
Mice
Mice, Nude
Mutation
Neoplasms / drug therapy
Phenylenediamines / chemical synthesis*
Phenylenediamines / pharmacology
Phenylenediamines / therapeutic use
Piperazines / chemistry*
Piperazines / pharmacology*
Piperazines / therapeutic use
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Signal Transduction / drug effects
Transplantation, Heterologous

Substances

2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)-N,N-dimethylethan-1-amine oxide
Acrylamides
Aniline Compounds
Antineoplastic Agents
Phenylenediamines
Piperazines
Protein Kinase Inhibitors
osimertinib
ErbB Receptors