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

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Abstract

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.

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Acknowledgements

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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Authors and Affiliations

  1. Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, People’s Republic of China

    Shuyu Jin & Dan Liu

  2. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Science, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, People’s Republic of China

    Shuyu Jin, Xiuyun Sun & Yu Rao

  3. Tsinghua-Peking Center for Life Sciences, Haidian Dist., Beijing, 100084, People’s Republic of China

    Xiuyun Sun

  4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People’s Republic of China

    Hua Xie

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  1. Shuyu Jin
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  2. Xiuyun Sun
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  3. Dan Liu
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  4. Hua Xie
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Correspondence to Dan Liu, Hua Xie or Yu Rao.

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Jin, S., Sun, X., Liu, D. et al. Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro. Chem. Pap. 73, 1333–1345 (2019). https://doi.org/10.1007/s11696-019-00686-0

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  • DOI: https://doi.org/10.1007/s11696-019-00686-0

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