Development and therapeutic potential of allosteric retinoic acid receptor-related orphan receptor ?t (ROR?t) inverse agonists for autoimmune diseases

The transcription factor retinoic acid receptor-related orphan receptor ?t (ROR?t) is an attractive drug target for some autoimmune diseases owing to its roles in the differentiation of human T helper 17 (Th17) cells which produce pro-inflammatory cytokine interleukin (IL)-17. ROR?t agonists and inverse agonists are classically targeted to the hydrophobic and highly conserved orthosteric binding pocket of ROR?t ligand binding domain (LBD). Although successful, this approach also brings some challenges, including off-target effects due to lack of selectivity over other nuclear receptors (NRs). Allosteric regulation of ROR?t by synthetic small molecules has recently emerged as novel research interests for its interesting modes of action (MOA), satisfying bioactivity profile and improved selectivity. In this review, we delineated the discovery and identification of the allosteric pocket of ROR?t. Subsequently, we focused on examples of small molecules that allosterically inhibit ROR?t, with a central attention on structural-activity-relationship (SAR) information, biological activity, pharmacokinetic (PK) property, and the ligand binding mode of these compounds. We also discussed the potential role of ROR?t allosteric inverse agonists as small molecule therapeutics for autoimmune diseases.

Automated summary

ROR?t, a transcription factor, is a potential drug target for autoimmune diseases due to its involvement in the differentiation of human Th17 cells. Allosteric regulation of ROR?t by small molecules has gained interest for its unique mode of action, bioactivity, and improved selectivity. This review discusses the discovery and identification of the allosteric pocket of ROR?t and provides examples of small molecules that allosterically inhibit ROR?t, including their SAR, biological activity, PK properties, and ligand binding mode. The potential role of ROR?t allosteric inverse agonists as small molecule therapeutics for autoimmune diseases is also explored.