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 - Funding Information:
We thank Kumar Kalurachchi for assistance with NMR studies and the NCI Developmental Therapeutics Program for conducing the NCI-60 cell line screens. The MD Anderson Cancer Center NMR Core Facility is supported in part by the NCI Cancer Center Support Grant (CA16672). S.K. is supported by the Larry Deaven Fellowship and a CPRIT research training grant (RP170067). Y.B. is supported by a CPRIT research training grant (RP210028), the Dr. John J. Kopchick Fellowship, and the Schissler Foundation. This work was funded by research grants from the American Cancer Society (RSG-15-145-01-CDD; F.L.M.), National Comprehensive Cancer Network (YIA170032; F.L.M.), Andrew Sabin Family Foundation (F.L.M.), Dr. Marnie Rose Foundation (F.L.M.), Uncle Kory Foundation (F.L.M.), University of Texas MD Anderson Cancer Center Institutional Research grant (F.L.M.), and the NIH (R01 CA231509-01A1; S.W.M.).
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 -