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

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

  • J Med Chem. 2022 Oct 27;65(20):13813-13832. doi: 10.1021/acs.jmedchem.2c01039.
Victoria C Yan 1,  Cong-Dat Pham 1,  Elliot S Ballato 1,  Kristine L Yang 1,  Kenisha Arthur 1,  Sunada Khadka 1 2,  Yasaman Barekatain 1 2,  Prakriti Shrestha 1,  Theresa Tran 1,  Anton H Poral 1,  Mykia Washington 1,  Sudhir Raghavan 1,  Barbara Czako 3,  Federica Pisaneschi 1,  Yu-Hsi Lin 1,  Nikunj Satani 1,  Naima Hammoudi 1,  Jeffrey J Ackroyd 1,  Dimitra K Georgiou 1,  Steven W Millward 1,  Florian L Muller 1
Affiliations

Affiliations

  • 1 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • 2 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • 3 Institute of Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
PMID: 36251833 DOI: 10.1021/acs.jmedchem.2c01039
Abstract

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 IC50 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.

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