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Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

  • Sharan R. Srinivasan
  • Hao Shao
  • Xiaokai Li
  • Jason E. GestwickiEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)

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.

Keywords

Allosteric inhibitors Chaperones Dihydropyrimidines MKT-077 Protein folding Protein–protein interactions Spergualin 

Notes

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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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Sharan R. Srinivasan
    • 1
  • Hao Shao
    • 2
  • Xiaokai Li
    • 2
  • Jason E. Gestwicki
    • 2
    Email author
  1. 1.Chemical Biology Graduate ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Department of Pharmaceutical ChemistryUniversity of California at San FranciscoSan FranciscoUSA

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