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

  • Chem Biol. 2013 Dec 19;20(12):1469-80. doi: 10.1016/j.chembiol.2013.10.008.
Anna Rodina  1 ,  Pallav D Patel  2 ,  Yanlong Kang  1 ,  Yogita Patel  3 ,  Imad Baaklini  3 ,  Michael J H Wong  3 ,  Tony Taldone  1 ,  Pengrong Yan  1 ,  Chenghua Yang  1 ,  Ronnie Maharaj  1 ,  Alexander Gozman  1 ,  Maulik R Patel  1 ,  Hardik J Patel  1 ,  William Chirico  4 ,  Hediye Erdjument-Bromage  5 ,  Tanaji T Talele  6 ,  Jason C Young  7 ,  Gabriela Chiosis  8
Affiliations
  • 1. Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • 2. Program 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.
  • 3. Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC H3G 0B1, Canada.
  • 4. Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
  • 5. Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • 6. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
  • 7. Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC H3G 0B1, Canada. Electronic address: [email protected].
  • 8. Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Electronic address: [email protected].
PMID: 24239008 DOI: 10.1016/j.chembiol.2013.10.008
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.

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