Altered states: selectively drugging the Hsp90 cancer chaperone
Abstract
The molecular chaperone Hsp90 is an exciting cancer drug target. The first Hsp90 inhibitor to enter clinical trials--the geldanamycin derivative 17AAG--has recently demonstrated proof-of-concept for successful target modulation, with sighs of therapeutic benefit. An important property of Hsp90 inhibitors is their ability to cause simultaneous, combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. However, the reason for therapeutic selectivity in cancer cells versus normal cells is unclear. New research now shows that Hsp90 exists in cancer cells in a heightened, activated state that is highly susceptible to inhibition by 17AAG.
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17-AAG is a GA derivative with reduced hepatotoxicity in stage II clinical trials for cancers, including prostate cancer.
“The Hsp90 inhibitor 17-AAG is a GA derivative with reduced hepatotoxicity in stage II clinical trials for cancers, including prostate cancer (34).”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [34]
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- Authors
- Workman, P.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Workman, Paul
- ORCID
- Workman, Paul
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2004-02
- Volume
- 10
- Issue
- 2
- Pages
- 47-51
- ISSN
- 1471-4914 (ISSN-L)
- OpenAlex
- W2136395938
- Cited by
- 195
- References
- 30
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 11 · 2015: 12 · 2014: 6 · 2013: 12 · 2012: 11
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- HSP90, Hsp90 inhibitors, 17-AAG, geldanamycin derivatives, cancer drug targets, protein degradation, molecular chaperones
- MeSH terms
- Antibiotics, Antineoplastic, Enzyme Inhibitors, Humans, Lactones, Neoplasms, Protein Binding, Quinones, Drug Design, Oncogene Proteins, Gene Expression Regulation, Neoplastic, Benzoquinones, Rifabutin, HSP90 Heat-Shock Proteins, Macrolides, Drug Resistance, Neoplasm, Lactams, Macrocyclic
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