Beyond the ligand-binding pocket: targeting alternate sites in nuclear receptors

Nuclear receptors (NRs) are a family of ligand-modulated transcription factors with significant therapeutic relevance from metabolic disorders and inflammation to cancer, neurodegenerative, and psychiatric disorders. Drug discovery efforts are typically concentrated on modulating the natural ligand action within the ligand-binding pocket (LBP) in the C-terminal ligand-binding domain (LBD). Drawbacks of LBP-based strategies include physiological alterations due to disruption of ligand binding and difficulties in achieving tissue specificity. Furthermore, the lack of a "pure" and predictable mechanism of action predisposes such intervention toward drug resistance. Recent outstanding progress in our understanding of NR biology has shifted the focus of drug discovery efforts from inside to outside the LBP, affording consideration to the interaction between NRs and coactivator proteins, the interaction between NRs and DNA and the NRs' ligand-independent functions. This review encompasses such currently available NR non-LBP-based interventions and their potential application in therapy or as specific tools to probe NR biology.