Summary for 9N9L
| Entry DOI | 10.2210/pdb9n9l/pdb |
| Descriptor | Nuclear receptor ROR-gamma, (5P)-5-[2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2-hydroxy-2-methylpropyl)-4-[(2S)-2-methylpyrrolidine-1-carbonyl]-1,3-thiazole-2-carboxamide (3 entities in total) |
| Functional Keywords | nuclear hormone receptor, nuclear protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 57860.46 |
| Authors | Spurlino, J.C.,Milligan, C. (deposition date: 2025-02-11, release date: 2025-04-30, Last modification date: 2025-05-07) |
| Primary citation | Kinzel, O.,Goldberg, S.D.,Cummings, M.D.,Gege, C.,Steeneck, C.,Xue, X.,Albers, M.,Schluter, T.,Kleymann, G.,Scott, B.,Sepassi, K.,Schoetens, F.,Venkatesan, H.,Tanis, V.M.,Coe, K.,Sales, Z.S.,Spurlino, J.,Milligan, C.,Fourie, A.M.,Edwards, J.P.,Hoffmann, T. Identification of JNJ-61803534, a ROR gamma t Inverse Agonist for the Treatment of Psoriasis. J.Med.Chem., 68:8713-8728, 2025 Cited by PubMed Abstract: The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a nuclear transcription factor expressed in both innate and adaptive immune cells, driving Th17 cell differentiation and IL-17 production. The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory diseases, and biologics that target IL-23/IL-17 signaling are efficacious in the treatment of psoriasis and psoriatic arthritis. RORγt, at the core of this pathway, represents an attractive opportunity for small-molecule intervention; however, combining high potency, nuclear receptor selectivity, and good physicochemical properties remains a challenge for RORγt inverse agonists. Recently, thiazole amides have been identified as potent RORγt inverse agonists; however, they often suffer from CYP450 autoinduction in the rat, precluding further development. Herein, we describe the discovery and development of potent and selective thiazole bisamide RORγt inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials. PubMed: 40237323DOI: 10.1021/acs.jmedchem.5c00390 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.637 Å) |
Structure validation
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