Drug-Mediated Targeted Disruption of Multiple Protein Activities Through Functional Inhibition of the Hsp90 Chaperone Complex

Stravopodis, Dimitrios; Margaritis, Lukas; Voutsinas, Gerassimos

doi:10.2174/092986707782793925

Cited by 74Heat shock proteins researchUbiquitin and proteasome pathwaysProtein Degradation and Inhibitors

Drug-Mediated Targeted Disruption of Multiple Protein Activities Through Functional Inhibition of the Hsp90 Chaperone Complex

Stravopodis, Dimitrios, Margaritis, Lukas, Voutsinas, Gerassimos·2007·Current Medicinal Chemistry

DOI 10.2174/092986707782793925

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Abstract

Hsp90 is an evolutionarily conserved and ubiquitously expressed molecular chaperone that mainly modulates, along with a group of co-chaperones, the general platform of protein folding and prevents the nonspecific aggregation of misfolded or unfolded proteins. In the voluminous Hsp90 clientele, a large variety of important regulatory proteins can be identified, including many whose deregulation may lead to cancer initiation and progression, such as the oncogenic clients pp60(v-src), Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1alpha and B-Raf. Therefore, inhibition of Hsp90 function offers the prospect of simultaneously disrupting multiple signaling pathways directly implicated in the development of malignant phenotypes. During the last few years, there has been a major focus on the development of Hsp90 specific inhibitors. This started with the discovery that certain natural products could specifically disrupt Hsp90 chaperone activities. The benzoquinone ansamycin antibiotic geldanamycin and its less toxic derivative 17-AAG have been shown to possess strong anti-proliferative and apoptotic activity in cancer cells, whereas 17-AAG has demonstrated potent anti-tumor activity in several human xenograft models, including breast, prostate and colon cancer. In an effort to overcome difficulties with drug toxicity and solubility, a number of novel bioengineered 17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule inhibitors, including purine and pyrazole derivatives, have emerged from rational drug design followed by high-throughput screening approaches. 17-AAG was the leader inhibitor to enter and successfully complete phase I clinical trials, thus demonstrating that Hsp90 constitutes a valid drug target for cancer therapy. This review includes information on the current model of ternary interactions between Hsp90, client proteins and a vast array of co-chaperones followed by a list of characteristic inhibitors and ongoing clinical trials reported thus far.

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HIF inhibitors identified to date lack specificity for specific blockade of HIF.
“One significant hurdle for the use of these compounds, however, is the lack of specificity of these compounds for specific blockade of HIF (such as digoxin, acriflavine, and 17-AAG) identified to date [124–126].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [124]

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Authors: Stravopodis, D., Margaritis, L., & Voutsinas, G.
Affiliations: National and Kapodistrian University of Athens (GR)
ORCID: Stravopodis, Dimitrios
Voutsinas, Gerassimos
Venue: Current Medicinal Chemistry
Publisher: Bentham Science Publishers Ltd.
Published: 2007-12-01
Volume: 14
Issue: 29
Pages: 3122-3138
ISSN: 0929-8673 (ISSN-L)
DOI: 10.2174/092986707782793925
OpenAlex: W2170427853
Cited by: 74
References: 0
Citations by year: 2025: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 5 · 2015: 6 · 2014: 6 · 2013: 5 · 2012: 6
FWCI: 3.97
Type: journal article
Language: en
Open access: closed
Locations: Current Medicinal Chemistry (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, molecular chaperones, geldanamycin, 17-AAG, 17-DMAG, IPI-504, Hsp90 co-chaperone, cancer therapy, drug design, clinical trials, protein folding
MeSH terms: Animals, Antineoplastic Agents, Humans, Neoplasm Proteins, Neoplasms, Drug Design, Signal Transduction, Benzoquinones, HSP90 Heat-Shock Proteins, Lactams, Macrocyclic

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Drug-Mediated Targeted Disruption of Multiple Protein Activities Through Functional Inhibition of the Hsp90 Chaperone Complex

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