SF2312 is a natural phosphonate inhibitor of enolase
Open accessAbstract
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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ENO1 undergoes homozygous deletion in 1-5% of GBM cancers; knockdown of ENO2 in ENO1-null GBM cells inhibits proliferation and intracranial tumorigenesis, whereas ENO1-expressing cancer cells are insensitive to ENO2 ablation.
“Similarly, the gene encoding enolase 1 (ENO1) is on the tumor-suppressor locus 1p36, and undergoes homozygous deletion in 1–5% of GBM cancers. Knockdown of enolase 2 (ENO2) in ENO1-null GBM cells resulted in significant inhibition of proliferation and intracranial tumorigenesis, whereas ENO1 expressing cancer cells were insensitive to ENO2 ablation.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Leonard et al., 2016
ENO1 loss results in extreme sensitivity to the pan-enolase inhibitor phosphonoacetohydroxamate and SF2312.
“Furthermore, ENO1 loss results in extreme sensitivity to the pan-enolase inhibitor phosphonoacetohydroxamate (PHAH) and SF2312 (Leonard et al., 2016; Muller et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Leonard et al., 2016
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References 38 · Cited by 96
- Authors
- 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.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-10-10
- Volume
- 12
- Issue
- 12
- Pages
- 1053-1058
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5110371
- OpenAlex
- W2530003115
- Cited by
- 96
- References
- 38
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 8 · 2017: 6 · 2016: 1
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (P01CA095616, P01CA120964, P30CA016672, P50CA127001, P30CA006516)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Organophosphorus compounds synthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- neuron-specific enolase, glioma, glycolysis inhibition, Micromonospora, structure-based drug design, ATP depletion, actinomycete secondary metabolites, X-ray crystal structure
- MeSH terms
- Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Models, Molecular, Phosphopyruvate Hydratase, Pyrrolidinones, Structure-Activity Relationship, Molecular Structure, Organophosphonates
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