A potent and selective RORγ inhibitor for the treatment of autoimmune diseases

Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp³ carbons (Fsp³). Initial structure-activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp³ compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.