Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors
| Autor: | Laszlo Orfi, Axel Ullrich, Bálint Szokol, Ferenc Baska, Pál Gyulavári, Tibor Vántus, Zoltán Greff, Robert Torka, Csaba Szántai-Kis, Zoltan Örfi, István Peták, Ibolya Kurko, Kinga Pénzes, György Kéri |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
C-Met
biology business.industry Organic Chemistry Pharmacology Biochemistry chemistry.chemical_compound Gefitinib Growth factor receptor chemistry Hepatocyte Growth Factor Receptor Drug Discovery medicine Cancer research biology.protein Cyclin-dependent kinase 8 ERBB3 Erlotinib Epidermal growth factor receptor business medicine.drug |
| Zdroj: | ACS Medicinal Chemistry Letters. 5:298-303 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml4003309 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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