Squalene Synthase Inhibitors

Abstract

Squalene synthase catalyzes the reductive dimerization of famesyl diphosphate (C-15) to form squalene, the C-30 polyisoprene precursor to cholesterol. In recent years, the search for inhibitors of squalene synthase for use as antihypercholesterolemic agents has intensified. The focus on this enzymatic transformation is due to the unique location of squalene synthase at the first step committed to sterols in the isoprene pathway. Selective inhibitors of this enzyme are expected to block cholesterol biosynthesis, without having deleterious effects on the branch pathways of isoprene biosynthesis. Potent inhibitors of squalene synthase have been discovered utilizing three of the major methods for drug discovery: rational design, synthetic chemical screening and natural products screening. These inhibitors have been shown to be potent and effective cholesterol lowering agents in animal models. This article will review the rationale for squalene synthase as a drug discovery target, recent advances in the biology of squalene synthase, and the progress toward clinically useful inhibitors of this key enzyme.

Unveiling the Therapeutic Potential of Squalene Synthase: Deciphering Its Biochemical Mechanism, Disease Implications, and Intriguing Ties to Ferroptosis

“…Its mRNA expression has been identified in most human organs; however, expression levels vary between them, with the highest being in the testis and skeletal muscle, while levels are low in the liver [5]. Within the cell, SQS is exclusively located in the smooth endoplasmic reticulum membrane, as observed in normal rat livers with immunoelectron microscopy [6]. Additionally, it is associated with the final branch point of the cholesterol biosynthesis pathway, also known as the mevalonate pathway, shown in Scheme 1.…”

“…This intermediate, PSPP, mediates the inflammatory response in neutrophils, where it inhibits oxygen radical production [7]. In the second half-reaction, PSPP is rearranged into squalene, an insoluble isoprenoid compound with a C 30 H 50 molecular formula that serves as the precursor for hormones, bile acids, and vitamin D, as shown in Scheme 1 [6]. In addition to the mevalonate pathway, squalene is part of the sterol biosynthesis pathway.…”

“…In addition to the mevalonate pathway, squalene is part of the sterol biosynthesis pathway. Therefore, squalene can take two possible routes after forming squalene epoxide via squalene epoxidase (SQLE): follow the mevalonate pathway to form cholesterol or follow the squalene dioxide pathway to form oxysterols [6,8].…”

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors

“…To avoid the above problems, we decided to inhibit the downstream step of farnesyl pyrophosphate synthesis in the cholesterol biosynthetic pathway, without interrupting the biosynthesis of essential nonsteroidal molecules …”

“…In the cholesterol biosynthetic cascade, squalene synthase is located downstream of HMG-CoA reductase and is the first enzyme involved in sterol biosynthesis . The inhibition of this enzyme prevents cholesterol biosynthesis without interrupting the production of farnesyl pyrophosphate, a substrate of nonsteroidal isoprenoid molecules . In other words, squalene synthase inhibitors have the potential to prevent adverse effects of statins.…”