Ubiquitin Ligase Idol Inhibitors for Treating Hypercholesterolemia

Despite widespread use of statins and other therapeutics, hypercholesterolemia remains a significant medical issue for a many patients unable to effectively regulate cholesterol levels. Cholesterol uptake is primarily mediated by the hepatic low density lipoprotein receptor (LDLR), which binds and internalizes plasma LDL. Elevated LDLR is associated with reduced LDL levels. Recently, the E3 ligase Idol (Inducible Degrader of LDLR) was shown to be a key regulator of LDLR levels. IDOL is a unique E3 ligase that utilizes its FERM domain to specifically target LDLR for polyubiquitylation and subsequent lysosomal degradation. Genetic ablation of IDOL raises levels of LDLR. Thus, inhibition of IDOL may be beneficial for the treatment of hypercholesterolemia. The ubiquitin‐proteasome system is a rich landscape for drug discovery. E3 ligases in particular are attractive therapeutic targets in various disorders, including metabolic disorders. Nevertheless, it has been challenging to discover and develop E3 ligase inhibitors as first in class clinical candidates. Here, we report the identification of novel IDOL inhibitors that modulate cellular cholesterol homeostasis. These compounds increased LDLR levels and increased LDL association in various cellular models. Biophysical characterization revealed direct binding of the compounds to IDOL and perturbation of IDOL:LDLR interactions. The most promising compounds were used as starting points to develop novel drug like molecules and the lead compounds are being evaluated in translational models of hypercholesterolemia. Data will be presented summarizing our progress to date targeting IDOL for the treatment of hypercholesterolemia. Work supported in part by NIH grant HL127893.