4ZJR

RORgamma in complex with inverse agonist 48

Summary for 4ZJR

• Entry DOI: 10.2210/pdb4zjr/pdb
• Descriptor: Nuclear receptor ROR-gamma, 6-chloro-4'-[(2-chloro-6-fluorobenzoyl)(methyl)amino]-3'-(2,2,2-trifluoroethoxy)biphenyl-3-carboxamide (3 entities in total)
• Functional Keywords: rorgamma ligand binding domain, inverse agonist, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 4
• Total formula weight: 106702.06

Authors

Marcotte, D.J. (deposition date: 2015-04-29, release date: 2015-06-17, Last modification date: 2023-09-27)

Primary citation

Chao, J.,Enyedy, I.,Van Vloten, K.,Marcotte, D.,Guertin, K.,Hutchings, R.,Powell, N.,Jones, H.,Bohnert, T.,Peng, C.C.,Silvian, L.,Hong, V.S.,Little, K.,Banerjee, D.,Peng, L.,Taveras, A.,Viney, J.L.,Fontenot, J.
Discovery of biaryl carboxylamides as potent ROR gamma inverse agonists.
Bioorg.Med.Chem.Lett., 25:2991-2997, 2015

PubMed Abstract: RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.

PubMed: 26048806
DOI: 10.1016/j.bmcl.2015.05.026

Experimental method

X-RAY DIFFRACTION (2.702 Å)