Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity
10.1016/j.apsb.2020.11.001
- Author:
Guoshun LUO
1
;
Zhenbang LI
1
;
Xin LIN
1
;
Xinyu LI
2
;
Yu CHEN
3
;
Kun XI
2
;
Maoxu XIAO
1
;
Hanlin WEI
1
;
Lizhe ZHU
2
;
Hua XIANG
1
Author Information
1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
2. School of Life and Health Sciences and Warshel Institute for Computational Biology, the Chinese University of Hong Kong, Shenzhen 518172, China.
3. Key Laboratory of Smart Drug Delivery, Ministry of Education School of Pharmacy, Fudan University, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
CRBN, cereblon;
CVD, cardiovascular disease;
Cholesterol reduction;
DC50, half degradation concentration;
ER, endoplasmic reticulum;
H&E, hematoxylin/eosin;
HDAC, histone deacetylase;
HMGCR;
HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase;
LDL-C, low-density lipoprotein cholesterol;
MFD, medium fat diet;
ORO, oil-red O;
Oral bioavailability;
PK, pharmacokinetic;
PROTAC, proteolysis-targeting chimera;
PROTACs;
SAR, structure–activity relationship;
TC, total cholesterol;
TG, triglyceride;
VHL, von Hippel-Lindau
- From:
Acta Pharmaceutica Sinica B
2021;11(5):1300-1314
- CountryChina
- Language:English
-
Abstract:
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 (
