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Withaferin A Analogs That Target the AAA+ Chaperone p97.
Tao, Shasha; Tillotson, Joseph; Wijeratne, E M Kithsiri; Xu, Ya-Ming; Kang, MinJin; Wu, Tongde; Lau, Eric C; Mesa, Celestina; Mason, Damian J; Brown, Robert V; Clair, James J La; Gunatilaka, A A Leslie; Zhang, Donna D; Chapman, Eli.
Afiliación
  • Tao S; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Tillotson J; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Wijeratne EMK; 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.
  • Xu YM; 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.
  • Kang M; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Wu T; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Lau EC; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Mesa C; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Mason DJ; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Brown RV; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Clair JJ; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Gunatilaka AAL; 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.
  • Zhang DD; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • Chapman E; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
ACS Chem Biol ; 10(8): 1916-1924, 2015 Aug 21.
Article en En | MEDLINE | ID: mdl-26006219
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Adenosina Trifosfatasas / Witanólidos / Antineoplásicos Fitogénicos Límite: Humans Idioma: En Revista: ACS Chem Biol Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Adenosina Trifosfatasas / Witanólidos / Antineoplásicos Fitogénicos Límite: Humans Idioma: En Revista: ACS Chem Biol Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos