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Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90
journal contribution
posted on 2023-06-08, 14:35 authored by Russell R A Kitson, Chuan-Hsin Chang, Rui Xiong, Huw E L Williams, Adrienne L Davis, William Lewis, Donna L Dehn, David Siegel, S Mark Roe, Chrisostomos ProdromouChrisostomos Prodromou, David Ross, Christopher J MoodyThe benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.
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Publication status
- Published
Journal
Nature ChemistryISSN
1755-4330Publisher
Nature Publishing GroupExternal DOI
Issue
4Volume
5Page range
307-314Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-03-12Usage metrics
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