Development of PCSK9 Inhibitors for Cardiovascular Diseases

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a liver-secreted protein whose activity indirectly raises blood levels of LDL cholesterol (LDL-C), an important risk factor for atherosclerosis and cardiovascular disease. Ace Therapeutics has a deep understanding of cardiovascular drug discovery and development. With the core purpose of advancing the industry, we are committed to providing the necessary technical support and research services for the development of PCSK9 inhibitors.

The Role of PCSK9 in Cardiovascular Diseases

PCSK9 is a key regulator of cholesterol metabolism that induces lysosomal degradation of the low-density lipoprotein (LDL) receptor in the liver and removes LDL-C from the circulation. Therefore, mutations in the PCSK9 gene may lead to elevated plasma cholesterol levels and increase the risk of atherosclerotic cardiovascular disease, which is thought to be one of the causes of familial hypercholesterolemia.

Fig. 1 Graphical illustration of the PCSK9 pleiotropic effects on platelet activation-induced MI. (Puteri MU, et al., 2022)

Current Status of PCSK9 Inhibitor Development

PCSK9 inhibitors are revolutionizing the management of cardiovascular and lipid disorders, offering hope for patients with complex dyslipidemia, primary hypercholesterolemia, non-ST segment elevation myocardial infarction (NSTEMI), acute coronary syndrome, and atherosclerosis. Below, we explore the latest advancements in PCSK9 inhibitor development, highlighting both marketed therapies and promising candidates currently in the pipeline.

PCSK9 Inhibitors in Development or Approved for the Treatment of Cardiovascular Diseases

Discovery of PCSK9 Inhibitors

Based on our professional technology platform, we can provide services for the development of different types of PCSK9 inhibitors.

• Small Molecule PCSK9 Inhibitor
  We are committed to supporting our clients in the development of innovative oral small molecule inhibitors targeting PCSK9. These cutting-edge therapies offer a promising alternative to injectable treatments, providing patients with a more convenient and accessible option for managing cholesterol levels.
• Monoclonal Antibody
  Monoclonal antibodies directed against PCSK9 have demonstrated remarkable efficacy in reducing LDL-C levels. To further advance this field, we can focus on optimizing existing antibody formulations or pioneering the development of next-generation monoclonal antibodies with enhanced therapeutic potential.
• Gene Silencing Therapy
  We empower our clients to explore next-generation gene silencing approaches, including small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), to unlock new possibilities in the treatment of dyslipidemia and cardiovascular diseases.

In Vitro Pharmacodynamic Studies

• PCSK9 Gene Expression Assay
  Liver cell lines, such as HepG2 or Huh7, provide a robust platform for investigating the impact of PCSK9 inhibitors on the regulation of PCSK9 gene expression. These models enable us to explore the molecular mechanisms underlying inhibitor efficacy and identify novel therapeutic targets.
• LDL Uptake Assay
  To evaluate the functional impact of PCSK9 inhibitors, we can conduct LDL uptake assays using hepatocyte cell lines like HepG2 or Huh7. This approach allows us to measure the LDL uptake capacity of liver cells and assess how PCSK9 inhibitors modulate this critical process, providing valuable insights into their therapeutic potential.

In Vivo Pharmacodynamic Studies

• Animal Model Development
  We can provide customized animal model construction services to help our clients better develop novel PCSK9 inhibitors.
  Animal Models of Atherosclerosis
  Animal Models of Thrombosis
  Animal Models of Heart Failure
  Transgenic Animal Models
• Effects on Hypercholesterolemia
  PCSK9 transgenic mice offer a powerful in vivo model to replicate the hypercholesterolemic conditions associated with human PCSK9 overexpression. By utilizing these models, we can investigate the modulatory effects of PCSK9 inhibitors on hypercholesterolemia, paving the way for the development of more effective treatments for cardiovascular diseases.
• Effect on Atherosclerosis
  To evaluate the therapeutic potential of PCSK9 inhibitors, we utilize ApoE-/- mice to construct robust animal models of atherosclerosis. These models enable us to assess the impact of PCSK9 inhibitors on arterial plaque formation, providing critical insights into their efficacy and mechanisms of action in vivo.

Ace Therapeutics, with long-standing experience in the field of cardiovascular disease, is able to provide clients with relevant drug discovery solutions to facilitate the development of novel PCSK9 inhibitors. If you are interested in our services, please do not hesitate to contact us.

1. Puteri, MU.; et al. PCSK9 Promotes Cardiovascular Diseases: Recent Evidence about Its Association with Platelet Activation-Induced Myocardial Infarction. Life, 2022: 12, 190.