Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro

  • Shuyu Jin
  • Xiuyun Sun
  • Dan LiuEmail author
  • Hua XieEmail author
  • Yu RaoEmail author
Original Paper


The discovery and development of a novel HER-2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer are presented in this article. EGFR family has been recognized as a crucial meditator in the cancer progression; HER-2 tyrosine kinase was one of the members among them. In the effort to explore potent HER-2 inhibitors, a novel series of 4-anilino-3-cyanoquinoline derivatives have been designed, synthesized and evaluated. Most compounds possessed modest proliferation inhibition on SK-BR-3 cell line and HER-2 kinase. Compound 16 appeared to be the most potent compound (HER-2 kinase IC50: 19.4 nM, SK-BR-3 IC50: 94 nM). In the experiment of cellular cytotoxicity assay, compound 16 shows a much lower cytotoxicity than neratinib on Beas-2b cell line (Human bronchial epithelial cells). In conclusion, compound 16 would be a promising lead compound for further anti-breast cancer drug discovery.


HER-2 inhibitors 4-Anilino-3-cyanoquinoline Covalent Anticancer activity 



This work was supported by National Natural Science Foundation of China (#81573277, 81622042, 81773567), National Major Scientific and Technological Special Project for “Significant New Drugs Development” (#SQ2017ZX095003) and Tsinghua University Initiative Scientific Research Program.


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Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2019

Authors and Affiliations

  1. 1.Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of EducationShenyang Pharmaceutical UniversityShenyangPeople’s Republic of China
  2. 2.MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Science, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijingPeople’s Republic of China
  3. 3.Tsinghua-Peking Center for Life SciencesBeijingPeople’s Republic of China
  4. 4.Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiPeople’s Republic of China

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