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Issue 7, 2012
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Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases

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Abstract

The regulation of chromatin structure and, therefore, transcriptional activity of histone proteins by reversible lysine acetylation is an important posttranslational modification. Inhibitors of histone deacetylase (HDAC) are considered as promising new anti-neoplastic drugs. The hydroxamic acid SAHA e.g. is currently used in the treatment of advanced primary cutaneous T-cell lymphoma. The EGFR protein tyrosine kinase inhibitor erlotinib is a prominent drug in cancer chemotherapy and currently approved for treatment of non-small cell lung cancer. In this report, we present a novel strategy for cancer drug development by a combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining two distinct pharmacological properties in one molecule, we expect a broader activity spectrum and less likelihood of drug resistance in cancer patients. The combination led to substances with both HDAC inhibitory properties and EGFR as well as HER2 kinase inhibitory activities.

Graphical abstract: Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases

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Publication details

The article was received on 23 Dec 2011, accepted on 06 May 2012 and first published on 08 May 2012


Article type: Concise Article
DOI: 10.1039/C2MD00317A
Med. Chem. Commun., 2012,3, 829-835

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    Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases

    T. Beckers, S. Mahboobi, A. Sellmer, M. Winkler, E. Eichhorn, H. Pongratz, T. Maier, T. Ciossek, T. Baer, G. Kelter, H. Fiebig and M. Schmidt, Med. Chem. Commun., 2012, 3, 829
    DOI: 10.1039/C2MD00317A

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