The neolignan-derived rexinoid LRK071

To maintain an organism functional, cells need to receive relevant information and respond to it. One option for signal reception and processing are nuclear receptors, which act as transcription factors after ligand (= signal) binding. Thus, the information about e.g. the availability of certain metabolites like fatty acids or cholesterol metabolites that act as receptor ligands is directly transformed into a change of gene expression pattern. In this way, cells and hence also the organism can respond to a changing metabolic status. The fact that this type of receptor binds and responds to ligands make it an ideal target for the development of drugs, e.g. in the treatment of metabolic disease. The so-called retinoid x receptor (RXR) forms heterodimers with other nuclear receptors and is able to regulate these receptors in a cooperative synergistic way if respective ligands are available. Receptors that can be co-regulated via RXR act as sensors for lipid metabolites and xenobiotics and are, therefore, important regulators of energy metabolism and detoxication. The development of strong synthetic ligands for those receptors showed the desired positive effects but also unwanted effects like lipid accumulation in liver and adipose tissue. RXR ligands with less efficacy (partial agonist) may co-regulate these receptors in a way that leads to less side effects. A systematic search for RXR ligands that was based on natural products and natural product analogs led us to a compound acting as selective partial agonist of RXR. In the proposed project we are focusing on the molecular mechanism of this compound. In addition, we will collect first data that show whether this compound is active in a whole organism. We expect from the collected data information as to whether this compound is suitable as a starting point for drug development. Moreover, we expect to generate knowledge that helps to better understand the role and regulation of RXR in cellular processes.