Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia

• Published in: Drug discovery today 2022-05, Vol.27 (5), p.1332-1349
• Main Authors: Ahamad, Shakir, Mathew, Shintu, Khan, Waqas A., Mohanan, Kishor
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Cholesterol, LDL - therapeutic use; Humans; Hypercholesterolemia - drug therapy; Low-density lipoprotein-cholesterol; PCSK9 Inhibitors; Proprotein Convertase 9; Protein–protein interaction inhibitors; Small-molecule drugs; United States
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2022.01.014

[Display omitted] •PCSK9 is a novel therapeutic target for preventing and treating atherosclerosis.•Two monoclonal antibodies to inhibit PCSK9 are already in the market.•Many small molecules targeting PCSK9 have been identified in the last decade.•Currently, no small molecule drug specific to PCSK9 is in the clinical trial.•Design and therapeutic effects of small molecule PCSK9 modulators are summarized. When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use. Subsequently, there have been tremendous efforts to develop cost-effective small molecules specific to PCSK9 over the past few years. These small molecules are promising therapeutics that act by preventing the synthesis of PCSK9, its secretion from cells, or the PCSK9–LDRL interaction. In this review, we summarize recent developments in the discovery of small-molecule PCSK9 inhibitors, focusing on their design, therapeutic effects, specific targets, and mechanisms of action.