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The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat
preprintsubmitted on 30.12.2020, 12:59 and posted on 31.12.2020, 07:56 by Ewen Calder, Anna Skwarska, Deborah Sneddon, Lisa Folkes, Ishna N. Mistry, Ester M. Hammond, Stuart Conway
The design and synthesis of four hypoxia-activated prodrugs of the KDAC inhibitor panobinostat is described. Initial validation of these compounds using isolated enzymes, and in two human cancer cell lines, reveals that the nitroimidazole-based prodrug (NI-Pano, CH-03) undergoes efficient bioreduction and fragmentation to release the parent drug, panobinostat. NI-Pano was identified as the optimum compound for use in further studies in cells, spheroid tumor models, and in vivo.
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