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Chem Biol. 2013 Dec 19;20(12):1469-80. doi: 10.1016/j.chembiol.2013.10.008. Epub 2013 Nov 14.

Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein.

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  • 1Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • 2Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
  • 3Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC H3G 0B1, Canada.
  • 4Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
  • 5Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • 6Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
  • 7Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC H3G 0B1, Canada. Electronic address: jason.young2@mcgill.ca.
  • 8Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Electronic address: chiosisg@mskcc.org.

Abstract

Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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