6NX1

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC CO-ACTIVATOR PEPTIDE AND COMPOUND-3 AKA 1,1,1,3,3,3-HEXAFLUORO-2-{4-[1-(4- LUOROBENZENESULFONYL)CYCLOPENTYL]PHENYL}PROPAN-2-OL

Summary for 6NX1

• Entry DOI: 10.2210/pdb6nx1/pdb
• Descriptor: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 fusion, 1,1,1,3,3,3-hexafluoro-2-(4-{1-[(4-fluorophenyl)sulfonyl]cyclopentyl}phenyl)propan-2-ol (3 entities in total)
• Functional Keywords: multiple binding modes, xenobiotic, promiscuous, nuclear hormone receptor, pxr, rorgt, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 80732.07

Authors

Khan, J.A. (deposition date: 2019-02-07, release date: 2020-02-12, Last modification date: 2024-03-13)

Primary citation

Duan, J.J.,Lu, Z.,Jiang, B.,Stachura, S.,Weigelt, C.A.,Sack, J.S.,Khan, J.,Ruzanov, M.,Galella, M.A.,Wu, D.R.,Yarde, M.,Shen, D.R.,Shuster, D.J.,Borowski, V.,Xie, J.H.,Zhang, L.,Vanteru, S.,Gupta, A.K.,Mathur, A.,Zhao, Q.,Foster, W.,Salter-Cid, L.M.,Carter, P.H.,Dhar, T.G.M.
Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active ROR gamma t Inverse Agonists.
Acs Med.Chem.Lett., 10:367-373, 2019

PubMed Abstract: A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide . Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at 1-position of the pyrrolidine ring and perfluoroisopropyl group at -position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1,4r)-4-(()-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (), which displayed excellent selectivity, desirable liability and pharmacokinetic properties , and a good pharmacokinetic profile in mouse. Oral administration of demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

PubMed: 30891142
DOI: 10.1021/acsmedchemlett.9b00010

Experimental method

X-RAY DIFFRACTION (2.27 Å)