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Updated: Apr 18, 2026
Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
Published on: July 21, 2021
Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer
Xiaokai Li1, Teresa Colvin2, Jennifer N Rauch1
1Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
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.
Insights
Researchers developed JG-98, a novel inhibitor targeting the Hsp70-Bag3 protein-protein interaction, to combat cancer. This approach shows promise by disrupting cancer cell survival pathways and demonstrating antiproliferative effects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Heat shock protein 70 (Hsp70) is crucial for cancer progression.
- Directly targeting Hsp70's active site is difficult.
- Hsp70 interacts with Bcl2-associated athanogene 3 (Bag3) to support cancer cell survival.
Purpose of the Study:
- To investigate the Hsp70-Bag3 protein-protein interaction (PPI) as a novel anticancer target.
- To evaluate the efficacy of JG-98, an inhibitor of the Hsp70-Bag3 PPI, against cancer cells.
Main Methods:
- Utilized JG-98, an allosteric inhibitor of the Hsp70-Bag3 PPI.
- Assessed JG-98's antiproliferative activity in various cancer cell lines.
- Examined JG-98's effects on FoxM1, p21, and p27 expression.
- Conducted in vivo studies in mice using xenograft models.
Main Results:
- JG-98 demonstrated significant antiproliferative activity (EC50: 0.3–4 μmol/L) across diverse cancer cell lines.
- JG-98 treatment led to FoxM1 destabilization and reduced suppression of p21 and p27.
- Pharmacokinetic and tolerability studies in mice were successful, with observed activity in xenograft models.
Conclusions:
- Inhibiting the Hsp70-Bag3 PPI represents a viable noncanonical strategy for cancer therapy.
- JG-98 shows potential as a therapeutic agent targeting this interaction.
- The Hsp70-Bag3 pathway is a promising new target for developing anticancer drugs.
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