Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783697769992552448 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8148065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT luoguoshun discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT lizhenbang discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT linxin discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT lixinyu discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT chenyu discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT xikun discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT xiaomaoxu discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT weihanlin discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT zhulizhe discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo AT xianghua discoveryofanorallyactivevhlrecruitingprotacthatachievesrobusthmgcrdegradationandpotenthypolipidemicactivityinvivo |