2. Academic Validation
  3. Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors

Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors

  • ACS Med Chem Lett. 2014 Jan 30;5(4):298-303. doi: 10.1021/ml4003309.
Bálint Szokol 1,  Pál Gyulavári 2,  Ibolya Kurkó 1,  Ferenc Baska 3,  Csaba Szántai-Kis 1,  Zoltán Greff 1,  Zoltán Orfi 4,  István Peták 5,  Kinga Pénzes 6,  Robert Torka 6,  Axel Ullrich 6,  László Orfi 7,  Tibor Vántus 2,  György Kéri 8
Affiliations

Affiliations

  • 1 Vichem Chemie Research Ltd. , 1022 Budapest, Hungary.
  • 2 MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University , 1085 Budapest, Hungary.
  • 3 Vichem Chemie Research Ltd. , 1022 Budapest, Hungary ; Rational Drug-Design Laboratory Cooperation Research Centre, Semmelweis University , 1085 Budapest, Hungary.
  • 4 Rational Drug-Design Laboratory Cooperation Research Centre, Semmelweis University , 1085 Budapest, Hungary ; Max Planck Institute of Biochemistry , Munich 82152, Germany.
  • 5 MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University , 1085 Budapest, Hungary ; KPS Medical Biotechnology and Healthcare Services Ltd. , 1022 Budapest, Hungary.
  • 6 Max Planck Institute of Biochemistry , Munich 82152, Germany.
  • 7 Vichem Chemie Research Ltd. , 1022 Budapest, Hungary ; Department of Pharmaceutical Chemistry, Semmelweis University , 1085 Budapest, Hungary.
  • 8 Vichem Chemie Research Ltd. , 1022 Budapest, Hungary ; MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University , 1085 Budapest, Hungary ; Rational Drug-Design Laboratory Cooperation Research Centre, Semmelweis University , 1085 Budapest, Hungary.
PMID: 24900830 DOI: 10.1021/ml4003309
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.

Keywords

EGFR; NSCLC; acquired resistance; c-Met; kinase inhibitor.

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