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Nat Chem Biol. 2016 Dec;12(12):1053-1058. doi: 10.1038/nchembio.2195. Epub 2016 Oct 10.

SF2312 is a natural phosphonate inhibitor of enolase.

Author information

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

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.

PMID:
27723749
PMCID:
PMC5110371
DOI:
10.1038/nchembio.2195
[Indexed for MEDLINE]
Free PMC Article

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