Abstract
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% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% O2). 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 pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
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•NI-Pano (CH-03) is reduced in an O2-dependent manner to release panobinostat•Treatment with NI-Pano in hypoxia leads to an accumulation of acetylated histones•NI-Pano increases cell death in hypoxic conditions but not normoxia•Treatment with NI-Pano led to tumor growth delay in a xenograft model
Skwarska, Calder et al. describe the design, synthesis, and biological testing of a hypoxia-activated KDAC inhibitor (NI-Pano, CH-03). NI-Pano is bioreduced in hypoxic conditions to release panobinostat, which leads to an accumulation in histone acetylation, increased cell death, and tumor growth delay.