SF2312 is a natural phosphonate inhibitor of enolase

Paul G. Leonard; Nikunj Satani; David Maxwell; Yu Hsi Lin; Naima Hammoudi; Zhenghong Peng; Federica Pisaneschi; Todd M. Link; Gilbert R. Lee; Duoli Sun; Basvoju A.Bhanu Prasad; Maria Emilia Di Francesco; Barbara Czako; John M. Asara; Y. Alan Wang; William Bornmann; Ronald A. Depinho; Florian L. Muller

doi:10.1038/nchembio.2195

SF2312 is a natural phosphonate inhibitor of enolase

Paul G. Leonard, Nikunj Satani, David Maxwell, Yu Hsi Lin, Naima Hammoudi, Zhenghong Peng, Federica Pisaneschi, Todd M. Link, Gilbert R. Lee, Duoli Sun, Basvoju A.Bhanu Prasad, Maria Emilia Di Francesco, Barbara Czako, John M. Asara, Y. Alan Wang, William Bornmann, Ronald A. Depinho, Florian L. Muller

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69 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1053-1058
Number of pages	6
Journal	Nature Chemical Biology
Volume	12
Issue number	12
DOIs	https://doi.org/10.1038/nchembio.2195
State	Published - Dec 1 2016

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Leonard, P. G., Satani, N., Maxwell, D., Lin, Y. H., Hammoudi, N., Peng, Z., Pisaneschi, F., Link, T. M., Lee, G. R., Sun, D., Prasad, B. A. B., Di Francesco, M. E., Czako, B., Asara, J. M., Wang, Y. A., Bornmann, W., Depinho, R. A., & Muller, F. L. (2016). SF2312 is a natural phosphonate inhibitor of enolase. Nature Chemical Biology, 12(12), 1053-1058. https://doi.org/10.1038/nchembio.2195

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title = "SF2312 is a natural phosphonate inhibitor of enolase",

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.",

author = "Leonard, {Paul G.} and Nikunj Satani and David Maxwell and Lin, {Yu Hsi} and Naima Hammoudi and Zhenghong Peng and Federica Pisaneschi and Link, {Todd M.} and Lee, {Gilbert R.} and Duoli Sun and Prasad, {Basvoju A.Bhanu} and {Di Francesco}, {Maria Emilia} and Barbara Czako and Asara, {John M.} and Wang, {Y. Alan} and William Bornmann and Depinho, {Ronald A.} and Muller, {Florian L.}",

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AU - Leonard, Paul G.

AU - Satani, Nikunj

AU - Maxwell, David

AU - Lin, Yu Hsi

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AU - Peng, Zhenghong

AU - Pisaneschi, Federica

AU - Link, Todd M.

AU - Lee, Gilbert R.

AU - Sun, Duoli

AU - Prasad, Basvoju A.Bhanu

AU - Di Francesco, Maria Emilia

AU - Czako, Barbara

AU - Asara, John M.

AU - Wang, Y. Alan

AU - Bornmann, William

AU - Depinho, Ronald A.

AU - Muller, Florian L.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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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SF2312 is a natural phosphonate inhibitor of enolase

Abstract

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