Project CHANCE is based on an earlier ERC CoG project in which a protein called IDOL was investigated. Increased levels of circulating low-density lipoprotein (LDL, so called "bad cholesterol") is a known risk factor for developing cardiovascular disease. We have shown that IDOL promotes the breakdown of the LDL-receptor (LDLR), and as such its activity increases LDL levels in the blood. Also, we have shown as part of the ERC CoG project that loss of IDOL in mice improves their overall metabolic health. It follows that inhibiting IDOL, which is the focus of CHANCE, may offer a novel strategy to improve metabolic health, and to increase the abundance of the LDLR and in doing so increase the clearance of LDL from plasma.
CHANCE build on our recently reported 3D structure of IDOL. In CHANCE we used this structure in conjunction with computational modelling to identify small molecules that can inhibit IDOL-mediated breakdown of the LDLR, as a strategy to identify potential IDOL inhibitors. Using a multistep computational algorithm we "screened" the ability of 1 million compounds to interact with IDOL. Of these, the top 1000 were selected for further testing and validation in cells. Using two independent set of experiments to measure IDOL activity we have now reduced the number of potential lead compounds to ~40. These are now being further evaluated for their IDOL inhibitory capacity in follow up studies, which will continue beyond the time frame of CHANCE.
CHANCE has initiated the search for effective IDOL inhibitors, an endeavour that is still ongoing. A set of potential lead IDOL inhibitors have been identified in CHANCE, which are being further investigated. Should any of these prove effective it may lead to the further development of IDOL inhibition as a strategy to combat metabolic and cardiovascular disease.
