9XMJ

A Potent and Selective ROR gamma Inhibitor for the Treatment of Autoimmune Diseases

This is a non-PDB format compatible entry.

Summary for 9XMJ

• Entry DOI: 10.2210/pdb9xmj/pdb
• Descriptor: Nuclear receptor ROR-gamma, Nuclear receptor corepressor 2, (4~{S})-4-[3-chloranyl-4-(2,2-dimethylpropoxy)phenyl]-~{N},~{N},6-trimethyl-2-oxidanylidene-3,4-dihydro-1~{H}-pyrimidine-5-carboxamide, ... (4 entities in total)
• Functional Keywords: il-17; autoimmune disease; ligand efficiency; fraction of sp3 carbon atoms, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 130936.72

Authors

Nomura, A.,Akai, S.,Yamaguchi, K.,Adachi, T. (deposition date: 2025-11-10, release date: 2026-04-29)

Primary citation

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.
A potent and selective ROR gamma inhibitor for the treatment of autoimmune diseases.
Bioorg.Med.Chem.Lett., 132:130494-130494, 2026

PubMed Abstract: 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 sp carbons (Fsp). 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 Fsp 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.

PubMed: 41371311
DOI: 10.1016/j.bmcl.2025.130494

Experimental method

X-RAY DIFFRACTION (2.18 Å)