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
  • 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.