6J1L

Crystal Structure Analysis of the ROR gamma(C455E)

6J1L の概要

• エントリーDOI: 10.2210/pdb6j1l/pdb
• 分子名称: Nuclear receptor ROR-gamma, 2-[4-(ethylsulfonyl)phenyl]-N-[2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)[1,1'-biphenyl]-4-yl]acetamide (3 entities in total)
• 機能のキーワード: ror gamma, lbd, inhibitor, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 95077.23

構造登録者

zhang, Y.,Li, C.C.,wu, X.S. (登録日: 2018-12-28, 公開日: 2019-05-01, 最終更新日: 2023-11-22)

主引用文献

Zhang, Y.,Wu, X.,Xue, X.,Li, C.,Wang, J.,Wang, R.,Zhang, C.,Wang, C.,Shi, Y.,Zou, L.,Li, Q.,Huang, Z.,Hao, X.,Loomes, K.,Wu, D.,Chen, H.W.,Xu, J.,Xu, Y.
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable ROR gamma Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer.
J.Med.Chem., 62:4716-4730, 2019

PubMed Abstract: We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.

PubMed: 30964293
DOI: 10.1021/acs.jmedchem.9b00327

実験手法

X-RAY DIFFRACTION (2.3 Å)