2. Academic Validation
  3. Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer

Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer

  • Mol Cancer Ther. 2015 Mar;14(3):642-8. doi: 10.1158/1535-7163.MCT-14-0650.
Xiaokai Li 1,  Teresa Colvin 2,  Jennifer N Rauch 1,  Diego Acosta-Alvear 3,  Martin Kampmann 4,  Bryan Dunyak 1,  Byron Hann 5,  Blake T Aftab 5,  Megan Murnane 5,  Min Cho 4,  Peter Walter 3,  Jonathan S Weissman 4,  Michael Y Sherman 2,  Jason E Gestwicki 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
  • 2 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
  • 3 Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
  • 4 Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
  • 5 Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
  • 6 Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. Jason.Gestwicki@ucsf.edu.
PMID: 25564440 DOI: 10.1158/1535-7163.MCT-14-0650
Abstract

HSP70 is a stress-inducible molecular chaperone that is required for Cancer development at several steps. Targeting the active site of HSP70 has proven relatively challenging, driving interest in alternative approaches. HSP70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across Cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for Anticancer therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117282
    99.88%, Hsp70 抑制剂
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