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Updated: Aug 7, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Discovery and development of purine-scaffold Hsp90 inhibitors
1Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA. chiosisg@mskcc.org
Abstract:
Hsp90 allows cancer cells to tolerate the many components of dysregulated pathways in a transformation-specific manner by interacting with several client substrates, such as kinases, hormone receptors and transcription factors that are directly involved in driving multistep malignancy, and also with mutated oncogenic proteins required for the transformed phenotype. This distinctive broad involvement in maintaining the transformed phenotype has suggested Hsp90 as an important target in cancer therapy. Discovery of pharmacological agents that selectively inhibit its function have aided in probing the biological functions of Hsp90 at the molecular level and in validating it as a novel target for anticancer drug action. Two natural product derivatives, 17-allylamino-17-desmethoxy-geldanamycin (17AAG) and 17-dimethylaminoethylamino-17-desmethoxy-geldanamycin (17DMAG) have further entered clinical trials, proving that Hsp90 may be modulated pharmacologically without causing target related toxicities in humans. In spite of their usefulness as proof-of-principle compounds, the clinical use of these two agents has been encumbered with some limitations due to their structural characteristics and also to less than optimal pharmacological profiles. Thus, the identification of Hsp90 inhibitors with improved structural characteristics and better pharmacological profiles is a major focus of interest in the field. One such emerging class is the purine-scaffold series. This review intends to inform the reader on efforts ranging from the discovery to their clinical translation.
Insights
Heat shock protein 90 (Hsp90) supports cancer cell survival and is a key target for cancer therapy. New purine-scaffold inhibitors offer improved Hsp90 inhibition for potential clinical use.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (Hsp90) is crucial for cancer cell survival by stabilizing client proteins involved in malignancy.
- Hsp90's broad role in maintaining the transformed phenotype makes it a significant therapeutic target in cancer treatment.
- Existing Hsp90 inhibitors, like 17AAG and 17DMAG, have shown proof-of-principle but face limitations in clinical application.
Purpose of the Study:
- To review the discovery and development of Hsp90 inhibitors.
- To highlight the potential of purine-scaffold compounds as next-generation Hsp90 inhibitors.
- To discuss the progression of these inhibitors from discovery to clinical translation.
Main Methods:
- Review of scientific literature on Hsp90 inhibitors.
- Analysis of drug discovery efforts focusing on Hsp90.
- Examination of clinical trial data for Hsp90-targeted agents.
Main Results:
- Hsp90 inhibitors demonstrate the feasibility of targeting Hsp90 pharmacologically without significant toxicity.
- Limitations of early Hsp90 inhibitors necessitate the development of agents with improved profiles.
- The purine-scaffold series represents a promising class of novel Hsp90 inhibitors.
Conclusions:
- Hsp90 remains a validated and important target for anticancer drug development.
- Ongoing research focuses on identifying Hsp90 inhibitors with enhanced structural and pharmacological properties.
- Purine-scaffold inhibitors are advancing towards clinical translation, offering new therapeutic avenues.
