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Identification and characterization of a novel small molecule agonist of lipoprotein lipase by random screening (654.12)

Elevated triglycerides and decreased HDL cholesterol are hallmarks of metabolic syndrome. Lipoprotein lipase (LPL) found lining the endothelium tissue in the adipose tissue, heart and muscle is an enzyme that catalyzes the hydrolysis of triglyceride rich lipoproteins and chylomicrons into free fatty acids. Regulation of LPL is a key physiological mechanism for the control of lipid levels and atherosclerosis risk. Angiopoietin‐like 4 (ANGPTL4) which inhibits the activity of LPL is a critical regulatory protein in LPL physiology and triglyceride metabolism. Currently, the most well characterized LPL agonist is NO‐1886. We screened an in‐house chemical library at a fixed concentration of 40µM in an in vitro LPL assay. Our screening identified a compound designated C10, showing LPL agonist activity equipotent to NO‐1886. Further, we determined that this novel LPL agonist is able to rescue the LPL inhibition by ANGPTL4, whereas NO‐1886 doesn’t rescue against ANGPTL4 inhibition. Additionally, we performed structure activity relationship study for C10 and identified a more potent LPL agonist (C10d) exhibiting at least 3 fold greater increase in LPL activity than NO‐1886. Our studies have identified a novel LPL agonist that can find therapeutic use in dyslipidemias associated with diabetes and cardio‐metabolic conditions like atherosclerosis.