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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.

Original publication




Journal article


Cell Chem Biol

Publication Date





1258 - 1270.e13


HAP, HDAC, KDAC, hypoxia, Animals, Antineoplastic Agents, Apoptosis, Cell Proliferation, Cell Survival, Drug Development, Drug Screening Assays, Antitumor, Female, Histone Deacetylase Inhibitors, Histone Deacetylases, Hypoxia, Male, Mice, Mice, Nude, Molecular Structure, Neoplasms, Experimental, Panobinostat, Tumor Cells, Cultured