SF2312 is a natural phosphonate inhibitor of enolase

  • Nat Chem Biol. 2016 Dec;12(12):1053-1058. doi: 10.1038/nchembio.2195.
Paul G Leonard  #  1 ,  Nikunj Satani  #  2 ,  David Maxwell  3 ,  Yu-Hsi Lin  2 ,  Naima Hammoudi  2 ,  Zhenghong Peng  4 ,  Federica Pisaneschi  2 ,  Todd M Link  1 ,  Gilbert R Lee 4th  1 ,  Duoli Sun  1 ,  Basvoju A Bhanu Prasad  1 ,  Maria Emilia Di Francesco  5 ,  Barbara Czako  5 ,  John M Asara  6 ,  Y Alan Wang  7 ,  William Bornmann  8 ,  Ronald A DePinho  7 ,  Florian L Muller  2
Affiliations
  • 1. Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
  • 2. Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
  • 3. Department of Clinical Analytics & Informatics, Houston, TX 77054-3403.
  • 4. Cardtronics, Inc., Houston, TX 77042.
  • 5. Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
  • 6. Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
  • 7. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA University of Texas MD Anderson Cancer Center, Houston, TX 77054 USA.
  • 8. Bayou Therapeutics, Inc, Missouri City, TX 77459-3028.
  • # Contributed equally.
PMID: 27723749 DOI: 10.1038/nchembio.2195
Abstract

Despite being crucial for energy generation in most forms of life, few if any microbial Antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme Enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding Enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Cα by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate Antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of Enolase.

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