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Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity |
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| Authors: | Dr Marc Pflieger Melf Sönnichsen Nadine Horstick-Muche Jing Yang Julian Schliehe-Diecks Andrea Schöler Prof Dr Arndt Borkhardt Dr Alexandra Hamacher Prof Dr Matthias U Kassack Prof Dr Finn K Hansen Dr Sanil Bhatia Prof Dr Thomas Kurz |
| Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany;2. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
These authors contributed equally to this work,;3. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany Department of Medicine, Yangzhou Polytechnic College, West Wenchang Road 458, Yangzhou, 225009 P.R. China;4. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany;5. Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany;6. Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany |
| Abstract: | The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan-histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk-benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6-selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea-based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea-based hydroxamic acids. Herein, we report highly potent N-alkoxyurea-based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastat A. |
| Keywords: | HDAC6 HDAC isozyme profile histone deacetylases inhibitors leukaemia |