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Published on: November 2, 2013
PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction
1Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, NY 10065, USA.
Abstract:
Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.
Insights
Novel synthetic Heat Shock Protein 90 (Hsp90) inhibitor PU-H71 shows promise for sustainable cancer remission. This purine analog offers a targeted approach, potentially overcoming toxicities of older therapies and enhancing chemotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Precision medicine advances have not consistently yielded long-term cancer remissions.
- Heat Shock Protein 90 (Hsp90) is a molecular chaperone with oncogenic properties and differential expression in cancer cells, making it a viable therapeutic target.
- Previous Hsp90 inhibitors derived from natural products exhibited off-target toxicities, necessitating the development of novel synthetic alternatives.
Purpose of the Study:
- To review the antineoplastic potential of the novel purine-based analog, PU-H71.
- To discuss PU-H71's efficacy in preclinical malignancy models and its current clinical evaluation.
- To explore potential combination therapies with PU-H71 for enhanced cancer treatment.
Main Methods:
- Review of preclinical data on PU-H71's efficacy in various cancer models.
- Analysis of PU-H71's mechanism of action as a synthetic Hsp90 inhibitor.
- Exploration of potential synergistic effects with other anticancer agents.
Main Results:
- PU-H71 demonstrates significant efficacy across multiple preclinical models of malignancy.
- The synthetic nature of PU-H71 suggests a potential for improved specificity and reduced toxicity compared to earlier inhibitors.
- Clinical trials are underway to further evaluate PU-H71's therapeutic benefit.
Conclusions:
- PU-H71 represents a promising novel therapeutic strategy for targeting Hsp90 in cancer treatment.
- Its synthetic design may overcome limitations of prior Hsp90 inhibitors.
- Concomitant therapeutic approaches involving PU-H71 could enhance outcomes for both molecular and traditional cancer chemotherapy.
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