title: Withaferin A Analogs That Target the AAA+ Chaperone p97.
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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tillotson
authors.affiliation: 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.
authors.forename: E M Kithsiri
authors.initials: EMK
authors.lastname: Wijeratne
authors.affiliation: 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.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: MinJin
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Lau
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Celestina
authors.initials: C
authors.lastname: Mesa
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Mason
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Brown
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: James J La
authors.initials: JJ
authors.lastname: Clair
authors.affiliation: 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.
authors.forename: A A Leslie
authors.initials: AAL
authors.lastname: Gunatilaka
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054358:Withanolides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009687:Nuclear Proteins; D054358:Withanolides; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; C009684:withaferin A