Biological and Medicinal Chemistry

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

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% 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.

Version notes

Version 2. Chemistry and biology combined.

Content

Thumbnail image of Skwarska, Calder et al TEXT.pdf

Supplementary material

Thumbnail image of Skwarska, Calder et al FIGURES.pdf
Skwarska, Calder et al FIGURES
Thumbnail image of Skwarska, Calder et al SI.pdf
Skwarska, Calder et al SI