Leveraging nuclear receptor mediated transcriptional signaling for drug discovery: Historical insights and current advances.

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression in response to physiological signals, such as hormones and other chemical messengers. These receptors either activate or repress the transcription of target genes, which in turn promotes or suppresses physiological processes governing growth, differentiation, and homeostasis. NRs bind to specific DNA sequences and, in response to ligand binding, either promote or hinder the assembly of the transcriptional machinery, thereby influencing gene expression at the transcriptional level. These receptors are involved in a wide range of pathological conditions, including cancer, metabolic disorders, chronic inflammatory diseases, and immune system-related disorders. Modulation of NR function through targeted drugs has shown therapeutic benefits in treating such conditions. NR-targeted drugs, which either completely or selectively activate or block receptor function, represent a significant class of clinically valuable therapeutics. However, the pathways of NR-mediated gene expression and the resulting physiological effects are complex, involving crosstalk between various biomolecular components. As a result, NR-targeted drug discovery is challenging. With improved understanding of how NRs regulate physiological functions and deeper insights into their molecular structure, the process of NR-targeted drug discovery has evolved. While many traditional NR-targeting drugs are associated with side effects of varying severity, new drug candidates are being designed to minimize these adverse effects. Given that NR activity varies according to the tissue in which they are expressed and the specific isoform that is activated or repressed, achieving selectivity in targeting specific tissues and isoform classes may help reduce systemic side effects. In a recent breakthrough, the isoform-selective, hepato-targeted thyroid hormone-β agonist, Resmetirom (marketed as Rezdiffra), was approved for the treatment of non-alcoholic steatohepatitis. This chapter explores the structural and mechanistic principles guiding NR-targeted drug discovery and provides insights into recent developments in this field.