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.
authors.affiliation: Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Leonard
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Nikunj
authors.initials: N
authors.lastname: Satani
authors.affiliation: Department of Clinical Analytics & Informatics, Houston, TX 77054-3403.
authors.forename: David
authors.initials: D
authors.lastname: Maxwell
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Yu-Hsi
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Naima
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Cardtronics, Inc., Houston, TX 77042.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Federica
authors.initials: F
authors.lastname: Pisaneschi
authors.affiliation: Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Link
authors.affiliation: Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Duoli
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Genomic Medicine and Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Basvoju A Bhanu
authors.initials: BAB
authors.lastname: Prasad
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Maria Emilia
authors.initials: ME
authors.lastname: Di Francesco
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Barbara
authors.initials: B
authors.lastname: Czako
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: 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.
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Bayou Therapeutics, Inc, Missouri City, TX 77459-3028.
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.affiliation: 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.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.
authors.forename: Florian L
authors.initials: FL
authors.lastname: Muller
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000618320:(1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011760:Pyrrolidinones; D010751:Phosphopyruvate Hydratase