2. Academic Validation
  3. Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities

Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities

  • Eur J Med Chem. 2019 Sep 1;177:32-46. doi: 10.1016/j.ejmech.2019.05.048.
Yue Su 1,  Ridong Li 2,  Xianling Ning 2,  Zhiqiang Lin 2,  Xuyang Zhao 2,  Juntuo Zhou 2,  Jia Liu 2,  Yan Jin 2,  Yuxin Yin 3
Affiliations

Affiliations

  • 1 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
  • 2 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
  • 3 Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, 100191, PR China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China. Electronic address: yinyuxin@hsc.pku.edu.cn.
PMID: 31129452 DOI: 10.1016/j.ejmech.2019.05.048
Abstract

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human Cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK Inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC50 values from 0.001 μM to 0.06 μM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC50 = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted Apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells.

Keywords

2,4-Diarylaminopyrimidine; Anti-angiogenesis; Anti-tumor activity; Dithiocarbamate; FAK inhibitors.

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