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Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as...

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Autores principales: Luo, Guoshun, Li, Zhenbang, Lin, Xin, Li, Xinyu, Chen, Yu, Xi, Kun, Xiao, Maoxu, Wei, Hanlin, Zhu, Lizhe, Xiang, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148065/
https://www.ncbi.nlm.nih.gov/pubmed/34094835
http://dx.doi.org/10.1016/j.apsb.2020.11.001
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author Luo, Guoshun
Li, Zhenbang
Lin, Xin
Li, Xinyu
Chen, Yu
Xi, Kun
Xiao, Maoxu
Wei, Hanlin
Zhu, Lizhe
Xiang, Hua
author_facet Luo, Guoshun
Li, Zhenbang
Lin, Xin
Li, Xinyu
Chen, Yu
Xi, Kun
Xiao, Maoxu
Wei, Hanlin
Zhu, Lizhe
Xiang, Hua
author_sort Luo, Guoshun
collection PubMed
description HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC(50) = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.
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spelling pubmed-81480652021-06-03 Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo Luo, Guoshun Li, Zhenbang Lin, Xin Li, Xinyu Chen, Yu Xi, Kun Xiao, Maoxu Wei, Hanlin Zhu, Lizhe Xiang, Hua Acta Pharm Sin B Original Article HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC(50) = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases. Elsevier 2021-05 2020-11-06 /pmc/articles/PMC8148065/ /pubmed/34094835 http://dx.doi.org/10.1016/j.apsb.2020.11.001 Text en © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Luo, Guoshun
Li, Zhenbang
Lin, Xin
Li, Xinyu
Chen, Yu
Xi, Kun
Xiao, Maoxu
Wei, Hanlin
Zhu, Lizhe
Xiang, Hua
Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title_full Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title_fullStr Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title_full_unstemmed Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title_short Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
title_sort discovery of an orally active vhl-recruiting protac that achieves robust hmgcr degradation and potent hypolipidemic activity in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148065/
https://www.ncbi.nlm.nih.gov/pubmed/34094835
http://dx.doi.org/10.1016/j.apsb.2020.11.001
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