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.

HMG-CoA还原酶（HMGCR）蛋白通常在他汀类药物（HMGCR抑制剂）治疗后被上调，这不可避免地降低了其治疗效果，从而引发了与副作用相关的更高剂量的需求。靶向嵌合体的蛋白水解（PROTAC）技术最近成为诱导蛋白质降解的有力方法。然而，由于其双功能性质，开发口服生物利用的PROTAC仍然是巨大的挑战。在这里，我们确定了一个强大的针对HMGCR的PROTAC（21c），其中包含与洛伐他汀酸偶联的VHL配体，可在Insig沉默的HepG2细胞中有效降解HMGCR（DC ₅₀ = 120 nmol / L）并形成稳定的三元复合物，这是通过整体建模协议确定的。最重要的是，口服给予相应的内酯21b使得亲本21b和转化酸21c均具有良好的血浆暴露。进一步的21b体内研究表明，饮食诱导的高胆固醇血症小鼠的HMGCR降解能力强，胆固醇有效降低，这突出了治疗高脂血症和相关疾病的一种有前途的策略。