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Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90

Nature Chemistry volume 5, pages 307–314 (2013)Cite this article

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Abstract

The 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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Figure 1: Trans–cis amide isomerization in geldanamycin BQAs.
Figure 2: Synthesis and reactivity of 19-substituted geldanamycin derivatives.
Figure 3: Overlaid crystal structures reveal the effect of 19-substitution on geldanamycin conformation and binding.
Figure 4: Structures of 19-substituted geldanamycins bound in the ATP site of yeast Hsp90, as determined by protein X-ray crystallography.
Figure 5: Evaluation of 19-substituted compounds as inhibitors of Hsp90 in cellular systems.

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Acknowledgements

The authors acknowledge support from the Parkinson's Disease Society UK (R.R.A.K. and C.J.M.). The work was also supported by the National Institutes of Health (NIH grants CA51210 and ES018943; D.R., D.S., C-H.C. and R.X.). The authors thank S. Aslam and K. Butler for help with NMR studies, and S. Young (University of Nottingham, ICPMS), M. Cooper and G. Coxhill (University of Nottingham, mass spectrometry) for technical assistance.

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Authors and Affiliations

  1. School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

    Russell R. A. Kitson, Huw E. L. Williams, Adrienne L. Davis, William Lewis & Christopher J. Moody

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, 80045, Colorado, USA

    Chuan-Hsin Chang, Rui Xiong, Donna L. Dehn, David Siegel & David Ross

  3. Genome Damage and Stability Centre, Science Park Road, University of Sussex, Falmer, BN1 9RQ, Brighton, UK

    S. Mark Roe & Chrisostomos Prodromou

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  1. Russell R. A. Kitson
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Contributions

D.R. and C.J.M. jointly conceived the project, and directed the biology and chemistry, respectively. R.R.A.K. was responsible for the design and execution of the chemistry. NMR studies and molecular modelling were carried out by R.R.A.K., H.E.L.W. and A.L.D., and W.L. carried out small-molecule X-ray crystallography. The biological studies were co-directed by D.S., and carried out by C-H.C., D.L.D. and R.X. Protein crystallography was directed by C.P. and carried out by C.P. and S.M.R. All authors contributed to the preparation of the manuscript.

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Correspondence to Chrisostomos Prodromou, David Ross or Christopher J. Moody.

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Kitson, R., Chang, CH., Xiong, R. et al. Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nature Chem 5, 307–314 (2013). https://doi.org/10.1038/nchem.1596

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