Development of Nuclear Receptor Modulators

With 49 members identified thus far, the superfamily of nuclear receptors offers a large number of targets to be pharmacologically exploited. Some nuclear receptors already look back to a successful history as drug targets, while others still lack any identified ligand. The development of small molecules targeting nuclear receptor is a challenging task and has to consider not only high affinity binding but also aspects as the nuclear localization of the target protein or transactivation efficacy. In this chapter, we summarize characteristics of nuclear receptors as target family, strategies of hit and lead identification, and the variety of methods for in vitro characterization of nuclear receptor modulators. A detailed method chapter describes an example optimization of a nuclear receptor modulator as well as hybrid reporter gene assays as a very flexible method of choice for in vitro characterization. Thereby, the chapter provides an introduction to nuclear receptor ligand development.