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

Guoshun Luo; Zhenbang Li; Xin Lin; Xinyu Li; Yu Chen; Kun Xi; Maoxu Xiao; Hanlin Wei; Lizhe Zhu; Hua Xiang

doi:10.1016/j.apsb.2020.11.001

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

Acta Pharm Sin B. 2021 May;11(5):1300-1314. doi: 10.1016/j.apsb.2020.11.001. Epub 2020 Nov 6.

Authors

Guoshun Luo¹, Zhenbang Li¹, Xin Lin¹, Xinyu Li², Yu Chen³, Kun Xi², Maoxu Xiao¹, Hanlin Wei¹, Lizhe Zhu², Hua Xiang¹

Affiliations

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.

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 (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.

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.