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Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor

preprint
revised on 21.03.2021, 16:04 and posted on 23.03.2021, 06:21 by Anna Skwarska, Ewen Calder, Deborah Sneddon, Hannah Bolland, Maria Odyniec, Ishna N. Mistry, Jennifer Martin, Lisa Folkes, Ester M. Hammond, Stuart Conway
Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% oxygen) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% oxygen). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub- micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our preclinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.

Funding

Chemical bioreductive approaches to targeted radiosensitisation and imaging of tumours

Medical Research Council

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Chemical biology tools for investigating the chemistry of cellular REDOX stress

Engineering and Physical Sciences Research Council

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History

Email Address of Submitting Author

stuart.conway@chem.ox.ac.uk

Institution

University of Oxford

Country

UK

ORCID For Submitting Author

0000-0002-5148-117X

Declaration of Conflict of Interest

None.

Version Notes

Version 2. Chemistry and biology combined.

Exports