6Q2W

Crystal structure of human ROR gamma LBD in complex with a quinoline sulfonamide inverse agonist

Summary for 6Q2W

• Entry DOI: 10.2210/pdb6q2w/pdb
• Descriptor: Nuclear receptor ROR-gamma, (2~{S})-1-[2,4-bis(chloranyl)-3-[[4-imidazol-1-yl-2-(trifluoromethyl)quinolin-8-yl]oxymethyl]phenyl]sulfonyl-~{N}-methyl-pyrrolidine-2-carboxamide (3 entities in total)
• Functional Keywords: ror gamma, inverse agonist, nuclear hormone receptor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 52972.80

Authors

Ciesielski, F.,Amaudrut, J.,Argiriadi, M.A.,Barth, M.,Breinlinger, E.C.,Calderwood, D.J.,Cusack, K.P.,Kort, M.E.,Montalbetti, C.,Potin, D.,Poupardin, O.,Spitzer, L. (deposition date: 2018-12-03, release date: 2019-05-29, Last modification date: 2024-01-24)

Primary citation

Amaudrut, J.,Argiriadi, M.A.,Barth, M.,Breinlinger, E.C.,Bressac, D.,Broqua, P.,Calderwood, D.J.,Chatar, M.,Cusack, K.P.,Gauld, S.B.,Jacquet, S.,Kamath, R.V.,Kort, M.E.,Lepais, V.,Luccarini, J.M.,Masson, P.,Montalbetti, C.,Mounier, L.,Potin, D.,Poupardin, O.,Rouaud, S.,Spitzer, L.,Wallace, C.D.
Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active ROR gamma inverse agonists.
Bioorg.Med.Chem.Lett., 29:1799-1806, 2019

PubMed Abstract: A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.

PubMed: 31101472
DOI: 10.1016/j.bmcl.2019.05.015

Experimental method

X-RAY DIFFRACTION (1.99 Å)