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

Thomas Beckers; Siavosh Mahboobi; Andreas Sellmer; Matthias Winkler; Emerich Eichhorn; Herwig Pongratz; Thomas Maier; Thomas Ciossek; Thomas Baer; Gerhard Kelter; Heinz-Herbert Fiebig; Mathias Schmidt

doi:10.1039/C2MD00317A

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

Thomas Beckers,‡^b Siavosh Mahboobi,*^a Andreas Sellmer,^a Matthias Winkler,^a Emerich Eichhorn,^a Herwig Pongratz,^a Thomas Maier,^b Thomas Ciossek,§ Thomas Baer,¶ Gerhard Kelter,^c Heinz-Herbert Fiebig^c and Mathias Schmidt*^b

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^a Department of Pharmaceutical Chemistry I, University of Regensburg, D-93040 Regensburg, Germany
E-mail: siavosh.mahboobi@chemie.uni-regensburg.de
Fax: +49 (0) 941-9431737
Tel: +49 (0) 941-9434824

^b Nycomed GmbH, a Takeda company, Byk-Gulden Strasse 2, D-78467 Konstanz, Germany

^c Oncotest GmbH, Institute for Experimental Oncology, Am Flughafen 12-14, D-79108 Freiburg, Germany

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.

MedChemComm

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

Abstract

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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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