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Identification of an irreversible PPARγ antagonist with potent anticancer activity

Melanoma is responsible for most skin cancer deaths, and its incidence continues to rise year after year. Different treatment options have been developed for melanoma depending on the stage of the disease. Despite recent advances in immuno‐ and targeted therapies, advanced melanoma remains incurable...

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Autores principales: Peng, Youyi, Zhang, Qiang, Zielinski, Robert M., Howells, Richard D., Welsh, William J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719157/
https://www.ncbi.nlm.nih.gov/pubmed/33280279
http://dx.doi.org/10.1002/prp2.693
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author Peng, Youyi
Zhang, Qiang
Zielinski, Robert M.
Howells, Richard D.
Welsh, William J.
author_facet Peng, Youyi
Zhang, Qiang
Zielinski, Robert M.
Howells, Richard D.
Welsh, William J.
author_sort Peng, Youyi
collection PubMed
description Melanoma is responsible for most skin cancer deaths, and its incidence continues to rise year after year. Different treatment options have been developed for melanoma depending on the stage of the disease. Despite recent advances in immuno‐ and targeted therapies, advanced melanoma remains incurable and thus an urgent need persists for safe and more effective melanoma therapeutics. In this study, we demonstrate that a novel compound MM902 (3‐(3‐(bromomethyl)‐5‐(4‐(tert‐butyl) phenyl)‐1H‐1,2,4‐triazol‐1‐yl) phenol) exhibited potent efficacies in inhibiting the growth of different cancer cells, and suppressed tumor growth in a mouse xenograft model of malignant melanoma. Beginning with MM902 instead of specific targets, computational similarity‐ and docking‐based approaches were conducted to search for known anticancer drugs whose structural features match MM902 and whose pharmacological target would accommodate an irreversible inhibitor. Peroxisome proliferator‐activated receptor (PPAR) was computationally identified as one of the pharmacological targets and confirmed by in vitro biochemical assays. MM902 was shown to bind to PPARγ in an irreversible mode of action and to function as a selective antagonist for PPARγ over PPARα and PPARδ. It is hoped that MM902 will serve as a valuable research probe to study the functions of PPARγ in tumorigenesis and other pathological processes.
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spelling pubmed-77191572020-12-11 Identification of an irreversible PPARγ antagonist with potent anticancer activity Peng, Youyi Zhang, Qiang Zielinski, Robert M. Howells, Richard D. Welsh, William J. Pharmacol Res Perspect Invited Reviews Melanoma is responsible for most skin cancer deaths, and its incidence continues to rise year after year. Different treatment options have been developed for melanoma depending on the stage of the disease. Despite recent advances in immuno‐ and targeted therapies, advanced melanoma remains incurable and thus an urgent need persists for safe and more effective melanoma therapeutics. In this study, we demonstrate that a novel compound MM902 (3‐(3‐(bromomethyl)‐5‐(4‐(tert‐butyl) phenyl)‐1H‐1,2,4‐triazol‐1‐yl) phenol) exhibited potent efficacies in inhibiting the growth of different cancer cells, and suppressed tumor growth in a mouse xenograft model of malignant melanoma. Beginning with MM902 instead of specific targets, computational similarity‐ and docking‐based approaches were conducted to search for known anticancer drugs whose structural features match MM902 and whose pharmacological target would accommodate an irreversible inhibitor. Peroxisome proliferator‐activated receptor (PPAR) was computationally identified as one of the pharmacological targets and confirmed by in vitro biochemical assays. MM902 was shown to bind to PPARγ in an irreversible mode of action and to function as a selective antagonist for PPARγ over PPARα and PPARδ. It is hoped that MM902 will serve as a valuable research probe to study the functions of PPARγ in tumorigenesis and other pathological processes. John Wiley and Sons Inc. 2020-12-05 /pmc/articles/PMC7719157/ /pubmed/33280279 http://dx.doi.org/10.1002/prp2.693 Text en © 2020 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Invited Reviews
Peng, Youyi
Zhang, Qiang
Zielinski, Robert M.
Howells, Richard D.
Welsh, William J.
Identification of an irreversible PPARγ antagonist with potent anticancer activity
title Identification of an irreversible PPARγ antagonist with potent anticancer activity
title_full Identification of an irreversible PPARγ antagonist with potent anticancer activity
title_fullStr Identification of an irreversible PPARγ antagonist with potent anticancer activity
title_full_unstemmed Identification of an irreversible PPARγ antagonist with potent anticancer activity
title_short Identification of an irreversible PPARγ antagonist with potent anticancer activity
title_sort identification of an irreversible pparγ antagonist with potent anticancer activity
topic Invited Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719157/
https://www.ncbi.nlm.nih.gov/pubmed/33280279
http://dx.doi.org/10.1002/prp2.693
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