Withaferin A Analogs That Target the AAA+ Chaperone p97

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1916-1924
Number of pages9
JournalACS Chemical Biology
Issue number8
StatePublished - Aug 21 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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