LXR Program

Selective modulators of LXRα (NR1H3) and LXRß (NR1H2) show great promises for the development of novel medications for lipid disorders, atherosclerosis and other metabolic complications. Potent full agonists of LXR have been shown to activate reverse cholesterol transport by inducing ABC transporter gene expression in macrophages and inhibit the formation of atherosclerotic lesions in animal models. Full LXR agonists do, however, also induce triglyceride synthesis in the liver, which is an obstacle for developing LXR ligands as therapeutics.

In the LXR lead generation program, Phenex has identified series of nonsteroidal compounds that activate cholesterol efflux in macrophages, but do not induce triglyceride synthesis in liver cells. Using Phenex' Selective Nuclear Receptor Modulator (SNuRM®) technology platform, we have analysed the molecular basis for the observed selective effects of our proprietary as well as other published LXR compounds.

The goal of Phenex' LXR program is twofold:

1.) We want to analyze the molecular basis for selective LXR modulators using our SNuRM® approach. Thereby we want to develop a rational based on cofactor profiling for the development of LXR compounds with pronounced anti-atherosclerotic effects and reduced triglyceride liability.

2.) Based on the outcome of step 1.), we aim in optimizing our compounds towards selective LXR modulators with an improved therapeutic ratio compared to full LXR agonists.