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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120909
    Hsp70 Inhibitor