biostudies-literatureSkwarska AMedical Research CouncilEPSRCEngineering and Physical Sciences Research Council1258-1270.e13https://www.ebi.ac.uk/biostudies/studies/S-EPMC8460716biostudies-literatureUnknown28(9)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 effecCell chemical biologyDevelopment and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor.PMC8460716MR/N009460/1EP/S019901/1Conway SJMartin JOdyniec MLSkwarska ACalder EDDMistry INSneddon DFolkes LKBolland HHammond EMfalseDevelopment and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor.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 effec2021-01-01T00:00:00Z2021 Sep2026-05-08T16:39:43.121Z2022-02-11T11:30:15.922ZS-EPMC84607163391002310.1016/j.chembiol.2021.04.004