The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer
Open accessAbstract
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.
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Cites
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HSP90 and the chaperoning of cancer
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Pathways of chaperone-mediated protein folding in the cytosol
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Structure and mechanism of the Hsp90 molecular chaperone machinery
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Self-citationATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo
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Self-citationIn Vivo Function of Hsp90 Is Dependent on ATP Binding and ATP Hydrolysis
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Trends in cancer incidence and mortality in Scotland: description and possible explanations
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HSP90 as a new therapeutic target for cancer therapy: the story unfolds
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Self-citationWORKMAN, P., BURROWS, F., NECKERS, L., & ROSEN, N. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1391.012 · Cited by 521
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Cited by
Apoptosis and Molecular Targeting Therapy in Cancer
Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y., & Sakuragi, N. (2014) · BioMed Research International · doi:10.1155/2014/150845 · Cited by 1,121
RetractedDrug discovery approaches targeting the PI3K/Akt pathway in cancer
Garcia-Echeverria, C., & Sellers, W. R. (2008) · Oncogene · doi:10.1038/onc.2008.246 · Cited by 473
The Hsp90 molecular chaperone: an open and shut case for treatment
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Self-citationBiophysics in drug discovery: impact, challenges and opportunities
Renaud, J.-P., Chung, C.-W., Danielson, U. H., Egner, U., Hennig, M., Hubbard, R. E., & Nar, H. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.123 · Cited by 382
Self-citationLambert, J.-P., Ivosev, G., Couzens, A. L., Larsen, B., Taipale, M., Lin, Z.-Y., Zhong, Q., Lindquist, S., Vidal, M., Aebersold, R., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2702 · Cited by 318
Metadata
- Authors
- Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., Collins, I., Davies, N. G. M., Drysdale, M. J., Dymock, B., Eccles, S. A., Finch, H., Fink, A., Hayes, A., Howes, R., Hubbard, R. E., James, K., Jordan, A. M., Lockie, A., Martins, V., Massey, A., Matthews, T. P., McDonald, E., Northfield, C. J., Pearl, L. H., Prodromou, C., Ray, S., Raynaud, F. I., Roughley, S. D., Sharp, S. Y., Surgenor, A., Walmsley, D. L., Webb, P., Wood, M., Workman, P., & Wright, L.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2007-11-20
- Volume
- 51
- Issue
- 2
- Pages
- 196-218
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1999715990
- Cited by
- 444
- References
- 49
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer. https://app.cochat.ai/papers/10.1021/jm701018h
- The paper
- Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., Collins, I., Davies, N. G. M., Drysdale, M. J., Dymock, B., Eccles, S. A., Finch, H., Fink, A., Hayes, A., Howes, R., Hubbard, R. E., James, K., Jordan, A. M., . . . Wright, L. (2008). 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm701018h
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
