SF2312 is a natural phosphonate inhibitor of Enolase
Leonard, Paul G.
Link, Todd M.
Lee, Gilbert R.
Prasad, Basvoju A. Bhanu
Di Francesco, Maria Emilia
Wang, Y. Alan
DePinho, Ronald A.
Muller, Florian L.Note: Order does not necessarily reflect citation order of authors.
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CitationLeonard, P. G., N. Satani, D. Maxwell, Y. Lin, N. Hammoudi, Z. Peng, F. Pisaneschi, et al. 2016. “SF2312 is a natural phosphonate inhibitor of Enolase.” Nature chemical biology 12 (12): 1053-1058. doi:10.1038/nchembio.2195. http://dx.doi.org/10.1038/nchembio.2195.
AbstractDespite being critical 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 for the treatment of cancers with deletion of Enolase 1, we modeled the synthetic tool compound inhibitor, Phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analogue of PhAH, with the hydroxamic nitrogen linked to the alpha-carbon 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 back-bone-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 nM inhibitor of Enolase.
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