Metabolic diseases refer to diseases caused by metabolic issues, resulting from factors such as metabolic disorders and hypermetabolism. These mainly include hypertension (HTN), type 2 diabetes mellitus (T2DM), hyperlipidemia (HLD), obesity, and non-alcoholic fatty liver disease (NAFLD). Multiple diseases among them may co-occur, share common risk factors, and are associated with an increased risk of disability, cancer, and premature death.
Studies have shown that the incidence of all metabolic diseases increased from 2000 to 2019, with the greatest burden observed in countries with higher average incomes, education levels, and fertility rates. Currently, the treatment of these diseases mainly relies on small-molecule drugs and targeted biologics. While these therapies demonstrate significant efficacy, they face limitations in terms of drug resistance, side effects, cost, and applicability, which indicates a need for new treatment methods.
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising technology in recent years, offering advantages such as targeting undruggable targets, high efficiency, and overcoming drug resistance. Advances have been made in applying PROTACs to metabolic disease-related targets such as HMGCR, PNPLA3, LXR, PI3K, and PDEδ.
PROTACs Targeting HMGCR
Cholesterol is the most abundant sterol molecule in mammals and is a fundamental component of cell membranes. Cholesterol homeostasis is crucial for normal physiological functions, and abnormalities in cholesterol metabolism are closely associated with the development of cardiovascular diseases, neurodegenerative diseases, and cancers.
Cholesterol synthesis primarily occurs in the liver through nearly 30 enzymatic reactions that convert acetyl-CoA into cholesterol. Among these steps, the mevalonate pathway mediated by 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is the key step in de novo cholesterol synthesis. Thus, the expression and regulation of HMGCR are vital for maintaining cholesterol homeostasis in the body.
HMGCR is a classical therapeutic target for statins in the prevention and treatment of cardiovascular diseases. However, statins can lead to compensatory upregulation of HMGCR protein and cause adverse effects, including skeletal muscle damage, highlighting the need for additional therapeutic strategies.
In 2020, Li et al. designed and synthesized a series of PROTAC molecules by linking atorvastatin with CRBN to target the degradation of HMGCR, a complex transmembrane protein located in the endoplasmic reticulum. Through a series of optimizations, they developed compound P22A, which effectively promotes the degradation of endogenous HMGCR protein. In Huh7 cells, HMGCR upregulation induced by P22A was significantly lower than that induced by atorvastatin. P22A also activates the sterol regulatory element-binding protein (SREBP) pathway and blocks cholesterol biosynthesis, providing a novel strategy for lowering cholesterol levels and treating related diseases.
Luo et al. developed a novel class of PROTACs targeting HMGCR by linking lovastatin with a VHL ligand. Among these, PROTAC 21c effectively degrades HMGCR in HepG2 cells and forms a stable ternary complex. Additionally, its corresponding orally bioavailable lactone, 21b, demonstrated favorable plasma exposure.
Further in vivo studies on 21b revealed potent HMGCR degradation and effective cholesterol-lowering effects in diet-induced hypercholesterolemic mice, highlighting a promising strategy for the treatment of hyperlipidemia and related diseases.
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