Nuclear Receptors as Targets for Drug Design: New Options and Old Challenges

Abstract

Steroid receptors, a subgroup of the superfamily of nuclear receptors (Gronemeyer and Laudet 1995), have been the target for pharmacological drug design since their recognition as “master genes” with pleiotropic action on various physiological processes (for a review see De Groot 1995). All nuclear receptors (NRs) are transcription factors regulating specific gene programs in response to binding of their cognate ligands through alteration of: (a) the activity of the basal transcription machinery, and (b) chromatin structure at target genes (Fig. 1). In addi-tion to this “direct” action, NRs can also mutually interfere, positively or negatively, with a number of other signaling processes (a poorly understood phenomenon, often referred to as “signal transduction crosstalk”; Fig. 1). Finally, as is increasingly recognized, NRs themselves can be targets for other signaling pathways and can be modified post-transcriptionally at specific sites, thereby modulating receptor activity.