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Updated: May 30, 2025
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Assessment of Hsp90β-selective inhibitor safety and on-target effects
Tyelor S Reynolds1, Sanket J Mishra1,2, Brian S J Blagg3
1Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN, 46556, USA.
Abstract:
The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of ~ 400 client proteins, many of which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, which inhibit all four Hsp90 isoforms, have been investigated in the clinic for the treatment of cancer. Unfortunately, detrimental side effects were observed and hindered the clinical development of pan-Hsp90 inhibitors. The two most common on-target toxicities, cardio-toxicity and ocular-toxicity, have been attributed to inhibition of the Hsp90α isoform. As an alternative strategy, Hsp90β-selective inhibitors have been developed, which have shown promising anti-cancer activity in vitro and in vivo in combination with immune-checkpoint blockade therapy. This study aims to assess the potential risks of cardio-toxicity and ocular-toxicity exhibited by Hsp90β-selective inhibitors in vitro. In summary, the Hsp90β-selective NDNB1182 was found to avoid the cardio- and ocular-toxicity typical of Hsp90 pan-inhibitors (e.g. 17-AAG), providing a promising path toward the generation of isoform-selective Hsp90 inhibitors.
Insights
Heat shock protein 90 beta (Hsp90β)-selective inhibitors show promise for cancer treatment by avoiding the toxic side effects associated with pan-Hsp90 inhibitors. These selective inhibitors offer a safer therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (Hsp90) chaperones are crucial for cancer cell survival and proliferation.
- Hsp90 pan-inhibitors, targeting all isoforms, face clinical hurdles due to dose-limiting toxicities like cardiotoxicity and ocular toxicity.
- These toxicities are linked to the inhibition of the Hsp90α isoform.
Purpose of the Study:
- To evaluate the cardiotoxicity and ocular toxicity risks of Hsp90β-selective inhibitors in vitro.
- To determine if Hsp90β-selective inhibitors can mitigate the side effects associated with Hsp90 pan-inhibitors.
- To assess the therapeutic potential of Hsp90β-selective inhibitors as a safer alternative in cancer treatment.
Main Methods:
- In vitro assessment of cardiotoxicity and ocular toxicity.
- Utilizing Hsp90β-selective inhibitors, specifically NDNB1182.
- Comparison with traditional Hsp90 pan-inhibitors (e.g., 17-AAG).
Main Results:
- The Hsp90β-selective inhibitor NDNB1182 demonstrated an absence of cardiotoxicity and ocular toxicity in vitro.
- These findings contrast with the known toxicities of Hsp90 pan-inhibitors.
- NDNB1182 shows potential for safe application in cancer therapy.
Conclusions:
- Hsp90β-selective inhibitors, such as NDNB1182, represent a promising strategy to overcome the limitations of Hsp90 pan-inhibitors.
- Isoform-selective inhibition of Hsp90 offers a potential path to develop safer and more effective cancer therapeutics.
- Further research into Hsp90β-selective agents could lead to improved cancer treatment outcomes with reduced side effects.
