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Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly
Abstract
Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Ralpha) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein-protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds.
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Citations
Cited by
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705
Self-citationSmall molecules, big targets: drug discovery faces the protein–protein interaction challenge
Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137
Virus entry: molecular mechanisms and biomedical applications
Dimitrov, D. S. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro817 · Cited by 701
Catalytic oxidation of carbohydrates into organic acids and furan chemicals
Zhang, Z., & Huber, G. W. (2018) · Chemical Society Reviews · doi:10.1039/c7cs00213k · Cited by 689
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497
Metadata
- Authors
- Braisted, A. C., Oslob, J. D., Delano, W. L., Hyde, J., McDowell, R. S., Waal, N., Yu, C., Arkin, M. R., & Raimundo, B. C.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2003-03-11
- Volume
- 125
- Issue
- 13
- Pages
- 3714-3715
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W1965451896
- Cited by
- 256
- References
- 0
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- closed
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- Braisted, A. C., Oslob, J. D., Delano, W. L., Hyde, J., McDowell, R. S., Waal, N., Yu, C., Arkin, M. R., & Raimundo, B. C. (2003). Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly. Journal of the American Chemical Society. https://doi.org/10.1021/ja034247i
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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