Withaferin A Analogs That Target the AAA+ Chaperone p97
Year: 2015
Type: article
Abstract: Understanding the mode of action (MOA) of many natural products can be puzzling with mechanistic clues that seem to lack a common thread. One such puzzle lies in the evaluation of the antitumor properties of the natural product withaferin A (WFA). A variety of seemingly unrelated pathways have been identified to explain its activity, suggesting a lack of selectivity. We now show that WFA acts as an inhibitor of the chaperone, p97, both in vitro and in cell models in addition to inhibiting the proteasome in vitro. Through medicinal chemistry, we have refined the activity of WFA toward p97 and away from the proteasome. Subsequent studies indicated that these WFA analogs retained p97 activity and cytostatic activity in cell models, suggesting that the modes of action reported for WFA could be connected by proteostasis modulation. Through this endeavor, we highlight how the parallel integration of medicinal chemistry with chemical biology offers a potent solution to one of natures' intriguing molecular puzzles.
Source: ACS Chemical Biology
Authors: Shasha Tao, Joseph Tillotson, E. M. Kithsiri Wijeratne, Ya-ming Xu, MinJin Kang, Tongde Wu, Eric C. Lau, Celestina Mesa, Damian J. Mason, Robert V. Brown, James J. La Clair, A. A. Leslie Gunatilaka, Donna D. Zhang, Eli Chapman
Institution: University of Arizona
Language: English
Subfield: Complementary and alternative medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Investigation of an anti-cancer phytochemical targeting Nrf2, G4181967753, Anticancer Agents from Plant- and Lichen-Associated Fungi of the Sonoran Desert, Stress response, p97, and Nrf2 in arsenic-mediated toxicity, Training in Environmental Toxicology of Human Disease, Southwest Environmental Health Sciences Center
OpenAlex ID: W375413697