Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1 -Deleted Cancers.

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 ( ENO1 ) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) ( 5 ), and its bis-pivaloyoxymethyl prodrug, POMHEX ( 6 ), in an ENO1 -deleted intracranial orthotopic xenograft model of glioblastoma [ Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1 -deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5 , exhibited low micromolar IC 50 values in ENO1 -deleted glioma cells and improved stability in human serum over 6 . The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.