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, I. Peták, Kinga Pénzes, Robert Torka, Axel Ullrich, L. Őrfi, T. Vántus, G. 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

Fingerprint

Epidermal Growth Factor Receptor
Cells
Non-Small Cell Lung Carcinoma
Proto-Oncogene Proteins c-met
Mutation
Phosphorylation
Protein-Tyrosine Kinases
Amplification
Genes
Western Blotting
Clinical Trials
Derivatives
Cell Line
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Szokol, B., Gyulavári, P., Kurkó, I., Baska, F., Szántai-Kis, C., Greff, Z., ... 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

Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors. / Szokol, Bálint; Gyulavári, Pál; Kurkó, Ibolya; Baska, Ferenc; Szántai-Kis, Csaba; Greff, Zoltán; Orfi, Zoltán; Peták, I.; Pénzes, Kinga; Torka, Robert; Ullrich, Axel; Őrfi, L.; Vántus, T.; Kéri, G.

In: ACS Medicinal Chemistry Letters, Vol. 5, No. 4, 10.04.2014, p. 298-303.

Research output: Contribution to journalArticle

Szokol, B, Gyulavári, P, Kurkó, I, Baska, F, Szántai-Kis, C, Greff, Z, Orfi, Z, Peták, I, Pénzes, K, Torka, R, Ullrich, A, Őrfi, L, Vántus, T & Kéri, G 2014, 'Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors', ACS Medicinal Chemistry Letters, vol. 5, no. 4, pp. 298-303. https://doi.org/10.1021/ml4003309
Szokol B, Gyulavári P, Kurkó I, Baska F, Szántai-Kis C, Greff Z et al. Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors. ACS Medicinal Chemistry Letters. 2014 Apr 10;5(4):298-303. https://doi.org/10.1021/ml4003309
Szokol, Bálint ; Gyulavári, Pál ; Kurkó, Ibolya ; Baska, Ferenc ; Szántai-Kis, Csaba ; Greff, Zoltán ; Orfi, Zoltán ; Peták, I. ; Pénzes, Kinga ; Torka, Robert ; Ullrich, Axel ; Őrfi, L. ; Vántus, T. ; Kéri, G. / Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 4. pp. 298-303.
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