9xmj
A Potent and Selective ROR gamma Inhibitor for the Treatment of Autoimmune Diseases
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedRetinoic acid receptor-related orphan receptor gamma (RORgamma) 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 sp(3) carbons (Fsp(3)). 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 RORgamma, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORgamma inhibitory potency along with LE, and Fsp(3) compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORgamma-targeted therapies. A potent and selective RORgamma inhibitor for the treatment of autoimmune diseases.,Ikenogami T, Yokota M, Fujioka S, Ogawa N, Noguchi M, Nomura A, Adachi T, Katsuda Y, Arita K, Miyagawa N, Aratsu Y, Asahina K, Crowe P, Tao H, Thacher S, Shiozaki M Bioorg Med Chem Lett. 2026 Mar;132:130494. doi: 10.1016/j.bmcl.2025.130494. Epub , 2025 Dec 8. PMID:41371311[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
