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Published on: November 2, 2015
Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor
Anna Skwarska1, Ewen D D Calder2, Deborah Sneddon2
1Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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.
Insights
A novel hypoxia-activated prodrug, 1-methyl-2-nitroimidazole panobinostat (NI-Pano), effectively targets and eliminates hypoxic tumor cells. Pre-clinical studies show NI-Pano selectively releases its active form in low-oxygen conditions, reducing tumor growth with minimal systemic toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Tumor hypoxia is a significant factor in cancer therapy resistance and poor patient outcomes.
- Hypoxia-activated prodrugs offer a targeted approach to treat tumors while minimizing damage to healthy tissues.
Purpose of the Study:
- To evaluate the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano), a novel bioreductive prodrug.
- To investigate NI-Pano's selective activation and therapeutic effects in hypoxic tumor models.
Main Methods:
- NI-Pano stability and bioreduction under normoxic and hypoxic conditions were assessed.
- In vitro studies involved treating 2D and 3D cell cultures to evaluate acetylation, apoptosis, and survival.
- In vivo efficacy was determined using tumor xenograft models in mice, with pharmacokinetic analysis.
Main Results:
- NI-Pano demonstrated stability in normoxia and selective release of panobinostat under hypoxia via NADPH-CYP reduction.
- In vitro, NI-Pano treatment increased histone acetylation, induced apoptosis, and reduced clonogenic survival.
- NI-Pano showed significant tumor growth delay in vivo, with detectable drug concentrations specifically in hypoxic xenografts.
Conclusions:
- NI-Pano exhibits potent anti-tumor activity by selectively targeting hypoxic tumor cells.
- Pre-clinical data support the clinical development of NI-Pano for treating hypoxic tumors.
- The drug's targeted activation minimizes systemic exposure, suggesting a favorable safety profile.
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