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Publication Abstract from PubMed

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 Calpha 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.

SF2312 is a natural phosphonate inhibitor of enolase.,Leonard PG, Satani N, Maxwell D, Lin YH, Hammoudi N, Peng Z, Pisaneschi F, Link TM, Lee GR 4th, Sun D, Prasad BA, Di Francesco ME, Czako B, Asara JM, Wang YA, Bornmann W, DePinho RA, Muller FL Nat Chem Biol. 2016 Oct 10. doi: 10.1038/nchembio.2195. PMID:27723749^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.