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

• 作者: Guoshun Luo Zhenbang Li Xin Lin Xinyu Li Yu Chen Kun Xi Maoxu Xiao Hanlin Wei Lizhe Zhu Hua Xiang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Original articles
• 页码范围: 1300-1314
• 页数: 15页
• 语种: 英文

摘要

HMG-CoA reductase(HMGCR)protein is usually upregulated after statin(HMGCR inhib-itor)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 prom-ising strategy for treating hyperlipidemia and associated diseases.