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The Right Tool for the Job: An Overview of Hsp90 Inhibitors

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HSF1 and Molecular Chaperones in Biology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1243))

Abstract

Molecular chaperones are responsible for maintaining intracellular protein quality control by facilitating the conformational maturation of new proteins as well as the refolding of denatured proteins. While there are several classes of molecular chaperones in the cell, this chapter will focus solely on the small molecule modulation of Hsp90, the 90 kDa heat shock protein. Hsp90 is not only responsible for folding nascent proteins, but it also regulates the triage of numerous client proteins through partnering with the ubiquitin-proteasome pathway. Consequently, Hsp90 plays critical role in maintaining the protein homeostasis (proteostasis) network within the cell and is required for the activation/maturation of more than 300 client protein substrates. Many of the clients that depend upon Hsp90 are overexpressed or mutated during malignant transformation. This often renders the clients thermodynamically unstable and dependent on Hsp90 for stability. This phenomenon results in an oncogenic ‘addiction’ to the Hsp90 protein folding machinery as Hsp90 maintains onco-client proteins. Furthermore, Hsp90-dependent substrates are associated with all ten hallmarks of cancer, making Hsp90 an attractive target for the development of cancer chemotherapeutics. In fact, 17 small molecule inhibitors of Hsp90 have been developed and clinically evaluated for the treatment of cancer. Unfortunately, most of these molecules have failed for various reasons, necessitating a new approach to modulate the Hsp90 protein folding machine.

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Acknowledgements

The authors gratefully acknowledge financial support from the National Institutes of Health (CA120458 and CA213566).

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The Warren Family Research Center for Drug Discovery and Development, The University of Notre Dame, Notre Dame, IN, USA

    John Koren III & Brian S. J. Blagg

Authors
  1. John Koren III
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  2. Brian S. J. Blagg
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Correspondence to Brian S. J. Blagg .

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Editors and Affiliations

  1. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Marc Laurence Mendillo

  2. University of Chicago, Chicago, IL, USA

    David Pincus

  3. Weizmann Institute of Science, Rehovot, Israel

    Ruth Scherz-Shouval

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Koren, J., Blagg, B.S.J. (2020). The Right Tool for the Job: An Overview of Hsp90 Inhibitors. In: Mendillo, M.L., Pincus, D., Scherz-Shouval, R. (eds) HSF1 and Molecular Chaperones in Biology and Cancer. Advances in Experimental Medicine and Biology, vol 1243. Springer, Cham. https://doi.org/10.1007/978-3-030-40204-4_9

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