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Withaferin A Analogs That Target the AAA+ Chaperone p97
Shasha Tao1, Joseph Tillotson1, E M Kithsiri Wijeratne2
1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
ACS Chemical Biology
|May 27, 2015
Summary
Withaferin A inhibits the chaperone p97 and the proteasome, impacting antitumor properties. Medicinal chemistry refined its activity toward p97, revealing proteostasis modulation as a unifying mechanism.
Area of Science:
- Natural product chemistry
- Chemical biology
- Molecular pharmacology
Background:
- The antitumor properties of withaferin A (WFA) are attributed to diverse, seemingly unrelated pathways.
- This lack of a common mechanistic thread suggests poor selectivity for WFA's biological targets.
Purpose of the Study:
- To elucidate the underlying mechanism of WFA's antitumor activity.
- To identify and refine WFA's molecular targets using medicinal chemistry and chemical biology approaches.
Main Methods:
- In vitro and cellular assays to assess WFA's inhibitory activity against p97 and the proteasome.
- Medicinal chemistry to develop WFA analogs with refined target specificity.
- Cell-based assays to evaluate the cytostatic activity of WFA analogs.
Main Results:
- Withaferin A was identified as an inhibitor of both p97 and the proteasome in vitro and in cell models.
- Medicinal chemistry efforts successfully refined WFA analogs to selectively inhibit p97 over the proteasome.
- Developed WFA analogs retained p97 inhibitory and cytostatic activities, linking diverse MOAs to proteostasis modulation.
Conclusions:
- Proteostasis modulation, through p97 inhibition, serves as a unifying mechanism for WFA's diverse antitumor activities.
- The integrated approach of medicinal chemistry and chemical biology effectively resolved the mechanistic puzzle of WFA.
- This study provides a framework for understanding and optimizing natural products with complex biological activities.