LXR Program

The oxysterol receptors LXRα (NR1H3) and LXRß (NR1H2) show great promises for the development of novel medications for atherosclerosis, Alzheimers Disease and other lipid mediated disorders. Potent full agonists of LXR have been shown to activate reverse cholesterol transport by inducing ABC transporter gene expression in macrophages and intestinal cells resulting in prevention and resolution of atherosclerotic lesions in several animal models. An obstacle to the development of LXR ligands as therapeutics is the induction of lipogenic enzymes in the liver mediated by both LXR subtypes.

Phenex has identified several series of nonsteroidal selective LXR modulators (sLXRMs) with submicromolar potencies that activate cholesterol efflux in human macrophages via induction of ABC transporters (e.g. ABCA1) but do not or merely induce triglyceride synthesis in human liver cells via induction of lipogenic enzymes (e.g. SREBP1c and FAS).

Using Phenex' Selective Nuclear Receptor Modulator (SNuRM®) cofactor profiling technology platform, we have identified molecular principles of action of these sLXRMs, enabling to build a rational path towards the identification of novel structural series with selective LXR modulator properties.

Phenex currently performs medicinal chemistry optimization for two sLXRM series with the primary goal of proof-of-concept studies in mouse atherosclerosis models.