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Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90
Abstract
Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.
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Cites
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502
Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E., & Neckers, L. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.18.8324 · Cited by 1,444
Bali, P., Pranpat, M., Bradner, J., Balasis, M., Fiskus, W., Guo, F., Rocha, K., Kumaraswamy, S., Boyapalle, S., Atadja, P., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500186200 · Cited by 755
Cited by
Drug 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
Pearl, L. H., Prodromou, C., & Workman, P. (2008) · Biochemical Journal · doi:10.1042/bj20071640 · Cited by 447
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., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701018h · Cited by 444
Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors
De Raedt, T., Walton, Z., Yecies, J. L., Li, D., Chen, Y., Malone, C. F., Maertens, O., Jeong, S. M., Bronson, R. T., Lebleu, V., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.014 · Cited by 258
Self-citationHeat-shock proteins: chaperoning DNA repair
Dubrez, L., Causse, S., Borges Bonan, N., Dumétier, B., & Garrido, C. (2020) · Oncogene · doi:10.1038/s41388-019-1016-y · Cited by 224
Metadata
- Authors
- Sydor, J. R., Normant, E., Pien, C. S., Porter, J. R., Ge, J., Grenier, L., Pak, R. H., Ali, J. A., Dembski, M. S., Hudak, J., Patterson, J., Penders, C., Pink, M., Read, M. A., Sang, J., Woodward, C., Zhang, Y., Grayzel, D. S., Wright, J., Barrett, J. A., Palombella, V. J., Adams, J., & Tong, J. K.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2006-11-14
- Volume
- 103
- Issue
- 46
- Pages
- 17408-17413
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2117807601
- Cited by
- 231
- References
- 3
- FWCI
- 10.07
- Type
- journal article
- Language
- en
- Open access
- closed
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- Sydor, J. R., Normant, E., Pien, C. S., Porter, J. R., Ge, J., Grenier, L., Pak, R. H., Ali, J. A., Dembski, M. S., Hudak, J., Patterson, J., Penders, C., Pink, M., Read, M. A., Sang, J., Woodward, C., Zhang, Y., Grayzel, D. S., Wright, J., . . . Tong, J. K. (2006). Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0608372103
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
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.
