HDL Probe 2

Technology

ML278 and ML279 are two of the inhibitors of SR-BI that were discovered in a high throughput screen. These molecules work by increasing the binding of HDL to SR-BI while reversibly inhibiting the transfer of cholesterol. ML278 and ML279 were shown to inhibit SR-B1 both selectively and potently in the screen assay with IC50s of 6 and 17 nM, respectively. It is important to note that these lead compounds showed superior potency in the screen assays compared to the clinical SR-B1 inhibitor ITX-5061.  

Problem Addressed

SR-BI is a member of CD36 superfamily, and is the primary receptor responsible for mediating selective transport of cholesterol between high-density lipoprotein (HDL) and cells. The mechanism of this transport is poorly understood but it is known to be dramatically different from classic endocytic uptake. In addition to cholesterol, SR-BI can also interact and transport a wide variety of other lipids and ligands. Thus, there is a need for molecular tools to probe the biology of SR-BI further.There are multiple potential therapeutic applications of SR-BI inhibitors. In addition to its significant influence on lipoprotein metabolism, SR-BI has been shown to influence a wide variety of physiologic and pathophysiologic systems, including hypercholesterolemia and coronary artery disease, female infertility, adrenal insufficiency, anemia, thrombocytopenia, endothelial dysfunction, immune/inflammatory defects, susceptibility to deep vein thrombosis and association with some cancers.  In addition, SR-BI acts as a co-receptor for cellular entry of HCV and malaria parasites.  In some of these cases (e.g., HCV and malarial infection, cancer), targeting SR-BI presents an attractive approach to therapy.

Advantages      

• ML278 and ML279 are selective, reversible, and potent inhibitors of SR-BI
• The lead compounds have superior potency compared to the clinical compound ITX-5061Inhibitors of SR-BI could be potential therapeutic agents to treat atherosclerosis and HCV and malarial infections.  

Publications

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport. ACS Medicinal Chemistry Letters 6, no. 4 (April 9, 2015): 375–380. Published online February 2, 2015. https://doi.org/10.1021/ml500154q.

Discovery of Bisamide-Heterocycles as Inhibitors of Scavenger Receptor BI (SR-BI)-Mediated Lipid Uptake. Bioorganic & Medicinal Chemistry Letters 25, no. 12 (June 15, 2015): 2594-2598. https://doi.org/10.1016/j.bmcl.2015.03.074. Published online April 11, 2015.