9n9l | pdb_00009n9l
An RORgt Inverse agonist for treatment of Psoriasis
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 PubMedThe retinoic acid receptor-related orphan receptor gamma t (RORgammat) 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. RORgammat, 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 RORgammat inverse agonists. Recently, thiazole amides have been identified as potent RORgammat 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 RORgammat inverse agonists that avoid autoinduction in the rat. This effort culminated in the discovery of JNJ-61803534, which advanced into phase 1 clinical trials. Identification of JNJ-61803534, a RORgammat Inverse Agonist for the Treatment of Psoriasis.,Kinzel O, Goldberg SD, Cummings MD, Gege C, Steeneck C, Xue X, Albers M, Schluter T, Kleymann G, Scott B, Sepassi K, Schoetens F, Venkatesan H, Tanis VM, Coe K, Sales ZS, Spurlino J, Milligan C, Fourie AM, Edwards JP, Hoffmann T J Med Chem. 2025 Apr 24;68(8):8713-8728. doi: 10.1021/acs.jmedchem.5c00390. Epub , 2025 Apr 16. PMID:40237323[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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