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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Overcoming cancer drug resistance through small-molecule targeting of HSP90 and HSP70
Ren-Duan Cai1, Ming-Jing Lin1, Qing-Mei Ye2,1
1These authors contributed equally to this work.
Abstract:
Heat shock proteins (HSPs) play a critical role in cancer progression and drug resistance by stabilizing oncoproteins, enhancing DNA repair, and modulating apoptosis pathways. In particular, HSP90 and HSP70 have been implicated in maintaining the survival of drug-resistant cancer cells. Consequently, targeting HSPs holds promise in combating drug resistance in cancers. HSP inhibitors induce apoptosis in resistant cancer cells and act as potent chemosensitizers, enhancing the efficacy of chemotherapy, radiotherapy, and targeted therapies. However, despite promising preclinical data, no HSP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) due to toxicity, limited treatment outcomes, or a lack of specificity. In this review, we attempted to provide a brief overview of small-molecule HSP inhibitors, including the medicinal chemistry of geldanamycin derivatives, resorcinol-based compounds, and purine-scaffold inhibitors. We summarized the recent advancements of HSP inhibitors, especially those in clinical trials, their mechanisms of action, and their combinations in overcoming multidrug resistance in cancers. Furthermore, we discussed the current challenges and proposed possible solutions.
Insights
Heat shock proteins (HSPs) are crucial in cancer drug resistance. Targeting HSPs with small-molecule inhibitors shows promise for enhancing cancer therapies, despite current challenges in clinical application.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock proteins (HSPs) critically influence cancer progression and drug resistance.
- HSP90 and HSP70 are key in the survival of drug-resistant cancer cells.
- Targeting HSPs offers a potential strategy to overcome cancer drug resistance.
Purpose of the Study:
- To review small-molecule HSP inhibitors for cancer therapy.
- To summarize advancements in HSP inhibitor development and clinical trials.
- To discuss mechanisms, combinations, challenges, and solutions for HSP inhibition in cancer.
Main Methods:
- Review of medicinal chemistry of HSP inhibitors (geldanamycin derivatives, resorcinol-based, purine-scaffold).
- Summary of recent advancements and clinical trial progress.
- Analysis of mechanisms of action and combination strategies.
Main Results:
- HSP inhibitors induce apoptosis and sensitize resistant cancer cells to various treatments.
- Several HSP inhibitors are in clinical trials, showing therapeutic potential.
- Challenges include toxicity, limited outcomes, and lack of specificity.
Conclusions:
- Small-molecule HSP inhibitors represent a promising therapeutic avenue for overcoming multidrug resistance in cancer.
- Further research and development are needed to address current challenges and optimize HSP inhibitor efficacy.
- Combination therapies involving HSP inhibitors may enhance treatment outcomes.
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