TY - JOUR
T1 - Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers
AU - Yan, Victoria C.
AU - Pham, Cong Dat
AU - Ballato, Elliot S.
AU - Yang, Kristine L.
AU - Arthur, Kenisha
AU - Khadka, Sunada
AU - Barekatain, Yasaman
AU - Shrestha, Prakriti
AU - Tran, Theresa
AU - Poral, Anton H.
AU - Washington, Mykia
AU - Raghavan, Sudhir
AU - Czako, Barbara
AU - Pisaneschi, Federica
AU - Lin, Yu Hsi
AU - Satani, Nikunj
AU - Hammoudi, Naima
AU - Ackroyd, Jeffrey J.
AU - Georgiou, Dimitra K.
AU - Millward, Steven W.
AU - Muller, Florian L.
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/10/27
Y1 - 2022/10/27
N2 - 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 IC50values 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.
AB - 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 IC50values 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.
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U2 - 10.1021/acs.jmedchem.2c01039
DO - 10.1021/acs.jmedchem.2c01039
M3 - Article
C2 - 36251833
AN - SCOPUS:85140326543
SN - 0022-2623
VL - 65
SP - 13813
EP - 13832
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -