2. Academic Validation
  3. Synthesis and anti-tumor efficacy of novel 2, 4-diarylaminopyrimidine derivatives bearing N-(3-pyridinylmethyl) urea moiety as anaplastic lymphoma kinase inhibitors

Synthesis and anti-tumor efficacy of novel 2, 4-diarylaminopyrimidine derivatives bearing N-(3-pyridinylmethyl) urea moiety as anaplastic lymphoma kinase inhibitors

  • Eur J Med Chem. 2019 Sep 15:178:141-153. doi: 10.1016/j.ejmech.2019.05.060.
Hong Chen 1,  Ridong Li 2,  Xianling Ning 2,  Xuyang Zhao 2,  Yan Jin 2,  Yuxin Yin 3
Affiliations

Affiliations

  • 1 Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 2 Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China.
  • 3 Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. Electronic address: yinyuxin@hsc.pku.edu.cn.
PMID: 31177074 DOI: 10.1016/j.ejmech.2019.05.060
Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on Other human tumor cell lines, which was different from Other ALK inhibitors.

Keywords

ALK inhibitor; Anti-proliferation activity; NSCLC; Structure modification.

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