The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat

31 December 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

Hypoxia
prodrugs
KDAC inhibitors
HDAC inhibitors
epigenetics
hypoxia-activated produgs

Supplementary materials

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Calder et al SI
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