Mechanistic studies of Sansalvamide A-amide: An allosteric modulator of Hsp90
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Herein we show that San A-amide, a structurally unique molecule, influences a subset of cancer-related pathways involving Hsp90. We show that San A-amide specifically binds to the N-middle domain of Hsp90 allosterically disrupts the binding of proteins thought to interact with the Hsp90 C-terminal domain, while having no effect on an N-terminal domain client protein. This unique mechanism suggests that San A-amide is a potential tool for studying C-terminal binding proteins of Hsp90 as well as a promising lead in the development of new cancer therapeutics.
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Sansalvamide A binds to the N-middle domain of HSP90 and allosterically inhibits protein complex formation necessary for promotion of tumor growth.
“Sansalvamide A binds to the N-middle domain of HSP90 and allosterically inhibits protein complex formation, which is necessary for promotion of tumor growth [187].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [187]
The paper reports that Sansalvamide A-amide binds preferentially to Hsp90’s N-middle domain and allosterically disrupts its interactions with the proteins IP6K2 and FKBP52 (Abstract). It distinguishes this derivative from Sansalvamide A itself, so it does not establish the stated mechanism for the unmodified compound. It links Hsp90 to cancer cell growth but does not establish that the particular disrupted complexes are necessary for tumor growth. (LLM, conf=0.87)
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Non-Pharmaceutical Interventions in Cancer Therapy
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Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis
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Allosteric Modulators of Heat Shock Protein 90 (HSP90)
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- Authors
- Vasko, R. C., Rodriguez, R. A., Cunningham, C. N., Ardi, V. C., Agard, D. A., & McAlpine, S. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- McAlpine, Shelli R.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-01-04
- Volume
- 1
- Issue
- 1
- Pages
- 4-8
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC2922868
- OpenAlex
- W2007103196
- Cited by
- 105
- References
- 39
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 11 · 2014: 12 · 2013: 8 · 2012: 8
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (R01CA137873)
- National Institute of General Medical Sciences (T34GM008303)
- Fogarty International Center (T37TW000067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HSP90, allosteric modulators, C-terminal domain, protein binding, cancer therapeutics, lead compounds, mechanism of action
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