7NP6
ROR(gamma)t ligand binding domain in complex with allosteric ligand FM257
Summary for 7NP6
| Entry DOI | 10.2210/pdb7np6/pdb |
| Descriptor | Nuclear receptor ROR-gamma, 4-[[3-[2-chloranyl-6-(trifluoromethyl)phenyl]-5-(1~{H}-pyrazol-4-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 | 29220.09 |
| Authors | Oerlemans, G.J.M.,Somsen, B.A.,de Vries, R.M.J.M.,Meijer, F.A.,Brunsveld, L. (deposition date: 2021-02-26, 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 Cited by 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: 34008974DOI: 10.1021/acs.jmedchem.1c00475 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.84 Å) |
Structure validation
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