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Bioreducible Pro-drug Inhibitors of Enolase
preprintsubmitted on 26.03.2020, 05:25 and posted on 26.03.2020, 10:28 by Victoria Yan, Kristine Yang, Elliot Ballato, Kenisha Arthur, Dimitra Georgiou, Florian Muller
Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of Enolase for cancers harboring deletions in ENO1. Here, we describe the application of nitroheterocycle pro-drugs capitalizing on tumor hypoxia. These bioreducible pro-drugs exhibit up to 14-fold greater potency under hypoxic conditions compared to normoxia and exhibit robust stability in biological fluids. Our work provides strong proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of Enolase inhibition.