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Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers.
Yan, Victoria C; Pham, Cong-Dat; Ballato, Elliot S; Yang, Kristine L; Arthur, Kenisha; Khadka, Sunada; Barekatain, Yasaman; Shrestha, Prakriti; Tran, Theresa; Poral, Anton H; Washington, Mykia; Raghavan, Sudhir; Czako, Barbara; Pisaneschi, Federica; Lin, Yu-Hsi; Satani, Nikunj; Hammoudi, Naima; Ackroyd, Jeffrey J; Georgiou, Dimitra K; Millward, Steven W; Muller, Florian L.
Affiliation
  • Yan VC; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Pham CD; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Ballato ES; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Yang KL; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Arthur K; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Khadka S; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Barekatain Y; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Shrestha P; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Tran T; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Poral AH; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Washington M; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Raghavan S; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Czako B; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Pisaneschi F; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Lin YH; Institute of Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Satani N; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Hammoudi N; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Ackroyd JJ; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Georgiou DK; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Millward SW; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
  • Muller FL; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
J Med Chem ; 65(20): 13813-13832, 2022 10 27.
Article in En | MEDLINE | ID: mdl-36251833
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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Full text: 1 Database: MEDLINE Main subject: Prodrugs / Glioblastoma / Organophosphonates / Glioma Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2022 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Prodrugs / Glioblastoma / Organophosphonates / Glioma Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2022 Type: Article Affiliation country: United States