Withaferin A Analogs That Target the AAA+ Chaperone p97

  • ACS Chem Biol. 2015 Aug 21;10(8):1916-1924. doi: 10.1021/acschembio.5b00367.
Shasha Tao  #  1 ,  Joseph Tillotson  #  1 ,  E M Kithsiri Wijeratne  2 ,  Ya-Ming Xu  2 ,  MinJin Kang  1 ,  Tongde Wu  1 ,  Eric C Lau  1 ,  Celestina Mesa  1 ,  Damian J Mason  1 ,  Robert V Brown  1 ,  James J La Clair  1 ,  A A Leslie Gunatilaka  2 ,  Donna D Zhang  1 ,  Eli Chapman  1
Affiliations
  • 1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • 2. Southwest Center for Natural Products Research and Commercialization, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States.
  • # Contributed equally.
PMID: 26006219 DOI: 10.1021/acschembio.5b00367
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.

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