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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
  • 22 Downloads

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.

Keywords

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

Notes

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.

References

  1. Awada A, Bozovic-Spasojevic I, Chow L (2012) New therapies in HER2-positive breast cancer: a major step towards a cure of the disease? Cancer Treat Rev 38:494–504.  https://doi.org/10.1016/j.ctrv.2012.01.001 CrossRefGoogle Scholar
  2. Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 28:1301–1307.  https://doi.org/10.1200/JCO.2009.25.8707 CrossRefGoogle Scholar
  3. Cortés JD, Dieras VM, Ro JM, Barriere JMM, Bachelot TM, Hurvitz SM, Le Rhun EM, Espié MM, Kim SM, Schneeweiss AM, Sohn JHM, Nabholtz JP, Kellokumpu-Lehtinen PP, Taguchi JM, Piacentini FM, Ciruelos EM, Bono PM, Ould-Kaci MM, Roux FM, Joensuu HP (2015) Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. 16:1700–1710. https://doi.org/10.1016/S1470-2045(15)00373-3
  4. Dzimitrowicz H, Berger M, Vargo C, Hood A, Abdelghany O, Raghavendra AS, Tripathy D, Valero V, Hatzis C, Pusztai L, Murthy R (2016) T-DM1 activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab and pertuzumab. J Clin Oncol 34:3511–3517.  https://doi.org/10.1200/JCO.2016.67.3624 CrossRefGoogle Scholar
  5. Eroglu Z, Tagawa T, Somlo G (2014) Human epidermal growth factor receptor family-targeted therapies in the treatment of HER2-overexpressing breast cancer. Oncologist 19:135–150.  https://doi.org/10.1634/theoncologist.2013-0283 CrossRefGoogle Scholar
  6. Ito Y, Suenaga M, Hatake K, Takahashi S, Yokoyama M, Onozawa Y, Yamazaki K, Hironaka S, Hashigami K, Hasegawa H, Takenaka N, Boku N (2012) Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a phase 1 dose-escalation study. Jpn J Clin Oncol 42:278–286.  https://doi.org/10.1093/jjco/hys012 CrossRefGoogle Scholar
  7. Jackson PA, Widen JC, Harki DA, Brummond KM (2017) Covalent modifiers: a chemical perspective on the reactivity of α, β-unsaturated carbonyls with thiols via hetero-michael addition reactions. J Med Chem 60:839–885.  https://doi.org/10.1021/acs.jmedchem.6b00788 CrossRefGoogle Scholar
  8. Li X, Yang C, Wan H, Zhang G, Feng J, Zhang L, Chen X, Zhong D, Lou L, Tao W, Zhang L (2017a) Discovery and development of pyrotinib: a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci 110:51–61.  https://doi.org/10.1016/j.ejps.2017.01.021 CrossRefGoogle Scholar
  9. Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer E, Naughton M, Goetz MP, Russell C, Tripathy D, Cobleigh M, Forero A, Pluard TJ, Anders C, Niravath PA, Thomas S, Anderson J, Bumb C, Banks KC, Lanman RB, Bryce R, Lalani AS, Pfeifer J, Hayes DF, Pegram M, Blackwell K, Bedard PL, Al-Kateb H, Ellis MJC (2017) Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res 23:5687–5695.  https://doi.org/10.1158/1078-0432.CCR-17-0900 CrossRefGoogle Scholar
  10. Mao Y, Zhu W, Kong X, Wang Z, Xie H, Ding J, Terrett NK, Shen J, Shen J (2013) Design, synthesis and biological evaluation of novel pyrimidine, 3-cyanopyridine and m-amino-N-phenylbenzamide based monocyclic EGFR tyrosine kinase inhibitors. Bioorg Med Chem 21:3090–3104.  https://doi.org/10.1016/j.bmc.2013.03.053 CrossRefGoogle Scholar
  11. Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Toma Evi Z, Denduluri N, Eparovi R, Gokmen E, Bashford A, Ruiz Borrego M, Kim S, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A (2017) Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18:1688–1700.  https://doi.org/10.1016/S1470-2045(17)30717-9 CrossRefGoogle Scholar
  12. Tiwari SR, Mishra P, Abraham J (2016) Neratinib, a novel HER2-targeted tyrosine kinase inhibitor. Clin Breast Cancer 16:344–348.  https://doi.org/10.1016/j.clbc.2016.05.016 CrossRefGoogle Scholar
  13. Tsou H, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang Y, Upeslacis J, Wissner A (2005) Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 48:1107–1131.  https://doi.org/10.1021/jm040159c CrossRefGoogle Scholar
  14. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Janne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 15:2552–2558.  https://doi.org/10.1158/1078-0432 CrossRefGoogle Scholar
  15. Yoshioka T, Shien K, Namba K, Torigoe H, Sato H, Tomida S, Yamamoto H, Asano H, Soh J, Tsukuda K, Nagasaka T, Fujiwara T, Toyooka S (2018) Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer. Cancer Sci 109:1166–1176.  https://doi.org/10.1111/cas.13546 CrossRefGoogle Scholar
  16. Zhang X, Peng T, Ji X, Li J, Tong L, Li Z, Yang W, Xu Y, Li M, Ding J, Jiang H, Xie H, Liu H (2013) Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor. Bioorg Med Chem 21:7988–7998.  https://doi.org/10.1016/j.bmc.2013.09.049 CrossRefGoogle Scholar

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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