HSP90 inhibitors: current development and potential in cancer therapy
Abstract
In the last decade, the molecular chaperone HSP90 has emerged as an important target in cancer therapeutics and has subsequently become the focus of several drug discovery and development efforts. The first-in-class HSP90 inhibitor 17-AAG entered into Phase I clinical trial in 1999. Today 13 HSP90 inhibitors representing multiple drug classes, with different modes of action, are undergoing clinical evaluation. The present review will highlight the involvement of HSP90 in regulating and maintaining the transformed phenotype, provide an overview on current HSP90 inhibitors and further update on the most relevant patents which have recently appeared in the literature. Keywords: Cancer therapeutics, cell surface, chaperoning, drug discovery, HSP90, signal transduction.
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No clinically approved HSP90 inhibitors exist, as most trials have been associated with limited efficacy and significant toxicity.
“However, to date, there are no clinically approved HSP90 inhibitors, as most trials have been associated with limited efficacy and significant toxicity”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [11]
HSP90 inhibition promotes degradation of different substrates in different tissues and rapidly induces stress responses that may mediate resistance.
“presumably because HSP90 inhibition promotes the degradation of different substrates in different tissues and rapidly induces stress responses that may mediate resistance.11”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [11]
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“Abbreviations 17-DR: 17-demethoxy-reblastatin; Akt: Serine/threonine kinase; ALT: Alanineaminotransferase; AST: Aspartate aminotransferase; BSA: Bovine serum albumin; CDK4: Cyclin dependent kinase 4; C-Raf: Raf proto-oncogene serine/threonineprotein kinase; DAPI: 4,6-diamidino-2-phenylindole; DMEM: Dulbecco’s modified…”
InfluentialPrada, E. T. A., & Auernhammer, C. J. (2017) · Endocrine Connections · doi:10.1530/ec-17-0286 · Cited by 29 · see citing works
Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain
Thirstrup, K., Sotty, F., Montezinho, L., Badolo, L., Thougaard, A., Kristjánsson, M., Jensen, T. N., Watson, S. P., & Nielsen, S. M. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.12.028 · Cited by 28 · see citing works
Role of the ER-induced UPR pathway, apoptosis, and autophagy in colorectal cancer
Beilankouhi, E. A. V., Sajadi, M. A., Alipourfard, I., Hassani, P., Valilo, M., & Safaralizadeh, R. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154706 · Cited by 31 · see citing works
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“17-AAG (Tanespimycin), an analog molecule chemically derived from GA, was the first HSP90 inhibitor to enter clinical trials [13].”
Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy
Xie, X., Zhang, N., Li, X., Huang, H., Peng, C. Y., Huang, W., Foster, L. J., He, G., & Han, B. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106721 · Cited by 27 · see citing works
Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis
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“ing study for their potential use as cancer therapy (15).”
BackgroundEvaluation of [11C]NMS-E973 as a PET tracer for in vivo visualisation of HSP90
Vermeulen, K., Naus, E., Ahamed, M., Attili, B. N. N. R., Siemons, M., Luyten, K., Celen, S., Schymkowitz, J. W. H., Rousseau, F., & Bormans, G. M. (2019) · Theranostics · doi:10.7150/thno.27213 · Cited by 26 · see citing works
“Many of these client proteins contribute to the six hallmarks of cancer [9].”
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“Wild-type EGFR has been shown to be a client protein of HSP90 [12] suggesting that their interaction is vital for the proliferation of EGFR-dependent cancers.”
BackgroundLiang, G., Liu, N., He, M., Yang, J., Liang, Z., Gao, X., Rahhal, A. H., He, Q., Zhang, H., & Zha, Z. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26260 · Cited by 26 · see citing works
“Thus, targeting HSP90 has been recognized as a promising strategy against cancers.(17) For example, inhibition of HSP90 by 17-AAG (an inhibitor of HSP90 which enters”
BackgroundMethodPalma, L. C., Ferreira, L. F., Petersen, A. L. D. O. A., Dias, B., de Menezes, J. P. B., Moreira, D. R. M., Hernandes, M. Z., & Veras, P. S. T. (2019) · Scientific Reports · doi:10.1038/s41598-019-51239-0 · Cited by 27 · see citing works
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“Synergy improves the efficiency of a therapy and could also help to reduce employed concentrations, thus avoiding side effects limiting clinical application [50].”
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“Cancer cells widely rely on Hsp90 to assist signal transduction, making Hsp90 a potential target for cancer therapy [34].”
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“Currently, there are thirteen Hsp90 inhibitors undergoing clinical developments and all Hsp90 inhibitors under clinical evaluation are classified into N-terminal inhibitors.(19) Despite the significant progress of this approach, N-terminal inhibitors induce the pro-survival heat shock response, which is speculated to…”
BackgroundNovel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling
Siddiqui, F. A., Parkkola, H., Vukić, V., Oetken-Lindholm, C., Jaiswal, A., Kiriazis, A., Pavic, K., Aittokallio, T. A., Salminen, T. A., & Abankwa, D. (2021) · Cancers · doi:10.3390/cancers13040927 · Cited by 22 · see citing works
“However, dose-limiting toxicity remains an issue, and may be intrinsic to ATP-competitive inhibitors [14], because these induce the heat shock response, which upregulates proteins like Hsp70 and Hsp90 itself, thus fueling a vicious cycle that demands ever greater inhibitor concentrations [15].”
BackgroundDevelopment and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor
Cruz, K. P., Patricio, B. F. D. C., Pires, V. C., Amorim, M. F., Pinho, A. G. S. F., Quadros, H. C., Dantas, D. A. S., Chaves, M. H. C., Formiga, F. R., Rocha, H. V. A., et al. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.644827 · Cited by 24 · see citing works
More than efficacy revealed by single-cell analysis of antiviral therapeutics
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- Authors
- Sidera, K., & Patsavoudi, E.
- Affiliations
- Pasteur Hellenic Institute (GR)
- Venue
- Recent Patents on Anti-Cancer Drug Discovery
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2013-12-13
- Volume
- 9
- Issue
- 1
- Pages
- 1-20
- ISSN
- 1574-8928 (ISSN-L)
- OpenAlex
- W4245469960
- Cited by
- 222
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 17 · 2022: 14 · 2021: 28 · 2020: 21 · 2019: 31 · 2018: 18 · 2017: 19 · 2016: 28 · 2015: 19 · 2014: 8 · 2013: 1
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Recent Patents on Anti-Cancer Drug Discovery (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 › Histone Deacetylase Inhibitors Research
- Keywords
- Hsp90 inhibitors, HSP90, molecular chaperones, cancer therapeutics, 17-AAG, drug discovery, clinical trials, patents, transformed phenotype, signal transduction, cell surface
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