Mahboobi, Siavosh and Sellmer, Andreas and Winkler, Matthias and Eichhorn, Emerich and Pongratz, Herwig and Ciossek, Thomas and Baer, Thomas and Maier, Thomas and Beckers, Thomas (2010) Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity. JOURNAL OF MEDICINAL CHEMISTRY, 53 (24). pp. 8546-8555. ISSN 0022-2623,
Full text not available from this repository. (Request a copy)Abstract
Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER-THERAPY; HDAC INHIBITORS; BETA; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Jul 2020 06:30 |
| Last Modified: | 06 Jul 2020 06:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/23726 |
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