7NEC

ROR(gamma)t ligand binding domain in complex with allosteric ligand FM217

Summary for 7NEC

• Entry DOI: 10.2210/pdb7nec/pdb
• Descriptor: Nuclear receptor ROR-gamma, 4-[[3-[2-chloranyl-6-(trifluoromethyl)phenyl]-5-(1~{H}-pyrrol-2-yl)-1,2-oxazol-4-yl]methoxy]benzoic acid (3 entities in total)
• Functional Keywords: nuclear receptor, retinoic acid receptor-related orphan receptor gamma t, inverse agonist, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29219.10

Authors

Somsen, B.A.,de Vries, R.M.J.M.,Meijer, F.A.,Brunsveld, L. (deposition date: 2021-02-03, release date: 2021-06-02, Last modification date: 2024-01-31)

Primary citation

Meijer, F.A.,Saris, A.O.W.M.,Doveston, R.G.,Oerlemans, G.J.M.,de Vries, R.M.J.M.,Somsen, B.A.,Unger, A.,Klebl, B.,Ottmann, C.,Cossar, P.J.,Brunsveld, L.
Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor gamma t.
J.Med.Chem., 64:9238-9258, 2021

PubMed Abstract: The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole () was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

PubMed: 34008974
DOI: 10.1021/acs.jmedchem.1c00475

Experimental method

X-RAY DIFFRACTION (1.95 Å)