4ZJR

RORgamma in complex with inverse agonist 48

4ZJR の概要

• エントリーDOI: 10.2210/pdb4zjr/pdb
• 分子名称: 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)
• 機能のキーワード: rorgamma ligand binding domain, inverse agonist, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P51449
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 106702.06

構造登録者

Marcotte, D.J. (登録日: 2015-04-29, 公開日: 2015-06-17, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.702 Å)