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Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, w...

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Detalles Bibliográficos
Autores principales: Griffett, Kristine, Burris, Thomas P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932051/
https://www.ncbi.nlm.nih.gov/pubmed/36817797
http://dx.doi.org/10.3389/fmed.2023.1102469
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author Griffett, Kristine
Burris, Thomas P.
author_facet Griffett, Kristine
Burris, Thomas P.
author_sort Griffett, Kristine
collection PubMed
description Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia.
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spelling pubmed-99320512023-02-17 Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases Griffett, Kristine Burris, Thomas P. Front Med (Lausanne) Medicine Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia. Frontiers Media S.A. 2023-02-02 /pmc/articles/PMC9932051/ /pubmed/36817797 http://dx.doi.org/10.3389/fmed.2023.1102469 Text en Copyright © 2023 Griffett and Burris. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Griffett, Kristine
Burris, Thomas P.
Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title_full Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title_fullStr Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title_full_unstemmed Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title_short Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases
title_sort development of lxr inverse agonists to treat mafld, nash, and other metabolic diseases
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932051/
https://www.ncbi.nlm.nih.gov/pubmed/36817797
http://dx.doi.org/10.3389/fmed.2023.1102469
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