Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors

Bálint Szokol, Pál Gyulavári, Ibolya Kurkó, Ferenc Baska, Csaba Szántai-Kis, Zoltán Greff, Zoltán Orfi, István Peták, Kinga Pénzes, Robert Torka, Axel Ullrich, László Orfi, Tibor Vántus, György Kéri

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.

Original languageEnglish
Pages (from-to)298-303
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 10 2014

Keywords

  • EGFR
  • NSCLC
  • acquired resistance
  • c-Met
  • kinase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Szokol, B., Gyulavári, P., Kurkó, I., Baska, F., Szántai-Kis, C., Greff, Z., Orfi, Z., Peták, I., Pénzes, K., Torka, R., Ullrich, A., Orfi, L., Vántus, T., & Kéri, G. (2014). Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors. ACS Medicinal Chemistry Letters, 5(4), 298-303. https://doi.org/10.1021/ml4003309