Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
| Autor: | Xin Lin, Hua Xiang, Lizhe Zhu, Zhenbang Li, Xinyu Li, Kun Xi, Yu Chen, Guoshun Luo, Hanlin Wei, Maoxu Xiao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
HMGCR
3-hydroxy-3-methylglutaryl coenzyme A reductase Statin medicine.drug_class PROTAC proteolysis-targeting chimera HDAC histone deacetylase RM1-950 Pharmacology Protein degradation Reductase CVD cardiovascular disease PK pharmacokinetic ER endoplasmic reticulum 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation PROTACs In vivo Oral administration Oral bioavailability SAR structure–activity relationship medicine General Pharmacology Toxicology and Pharmaceutics CRBN cereblon 030304 developmental biology HMGCR 0303 health sciences TG triglyceride Chemistry Proteolysis targeting chimera MFD medium fat diet H&E hematoxylin/eosin DC50 half degradation concentration TC total cholesterol VHL von Hippel-Lindau Cholesterol reduction 030220 oncology & carcinogenesis Original Article LDL-C low-density lipoprotein cholesterol lipids (amino acids peptides and proteins) Therapeutics. Pharmacology Lovastatin Acid ORO oil-red O |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 5, Pp 1300-1314 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | 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 (DC50 = 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. Graphical abstract The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. A potent and orally active VHL-recruiting PROTAC was developed, displaying robust HMGCR degradation and potent hypolipidemic activity in diet-induced mice.Image 1 |
| Databáze: | OpenAIRE |
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