Toward Tumor-Conditional Release of Histone Deacetylase Inhibitors from Nongenotoxic Drug Conjugates

Abstract Inhibition of histone deacetylase (HDAC) metalloenzymes with hydroxamic acid-based inhibitors is compromised by generally poor metalloenzyme selectivity and the potential for genotoxicity arising from isocyanate metabolites. Here, we applied our previously described platform for iron(II)-activatable drug delivery to the pan-HDAC inhibitor panobinostat and its study in multiple myeloma cell line models. We demonstrate successful caging of HDAC activity in conjugate form, as well as mitigation of genotoxicity in a bioisosteric control. Finally, we identify the carboxy esterase CES1 as being responsible for unexpected proteolytic instability of the panobinostat conjugate in vitro and in vivo, identifying a focus for future work toward the ultimate goal of mitigating hydroxamate toxicity and mutagenicity through tumor-conditional activation.