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Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

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Heat Shock Protein Inhibitors

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 19))

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Abstract

Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein–protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

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Acknowledgments

Our work on Hsp70 is funded by the NIH (NS059690). We thank the members of our group for useful feedback and advice.

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Authors and Affiliations

  1. Chemical Biology Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA

    Sharan R. Srinivasan

  2. Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, 94158, USA

    Hao Shao, Xiaokai Li & Jason E. Gestwicki

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  1. Sharan R. Srinivasan
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  2. Hao Shao
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  3. Xiaokai Li
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  4. Jason E. Gestwicki
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Correspondence to Jason E. Gestwicki .

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Editors and Affiliations

  1. School of Chemistry, University of New South Wales, Sidney, New South Wales, Australia

    Shelli R. McAlpine

  2. Biomedical Biotechnology Research Unit (BioBRU); Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa

    Adrienne Lesley Edkins

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Srinivasan, S.R., Shao, H., Li, X., Gestwicki, J.E. (2015). Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis. In: McAlpine, S., Edkins, A. (eds) Heat Shock Protein Inhibitors. Topics in Medicinal Chemistry, vol 19. Springer, Cham. https://doi.org/10.1007/7355_2015_88

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