7XQE

Crystal Structure of human RORgamma (C455E) LBD in complex with compound XY039

7XQE の概要

• エントリーDOI: 10.2210/pdb7xqe/pdb
• 分子名称: Nuclear receptor ROR-gamma, 2,4-difluoro-N-(1-((4-(trifluoromethyl)benzyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide, GLYCEROL, ... (5 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: 2
• 化学式量合計: 63673.26

構造登録者

Wu, X.,Li, C.,Zhang, Y.,Xu, Y. (登録日: 2022-05-07, 公開日: 2023-05-31, 最終更新日: 2024-06-12)

主引用文献

Wu, X.S.,Luo, X.Y.,Li, C.C.,Zhao, X.F.,Zhang, C.,Chen, X.S.,Lu, Z.F.,Wu, T.,Yu, H.N.,Peng, C.,Hu, Q.Q.,Shen, H.,Xu, Y.,Zhang, Y.
Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as ROR gamma inverse agonists against prostate cancer.
Acta Pharmacol.Sin., 2024

PubMed Abstract: The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

PubMed: 38698214
DOI: 10.1038/s41401-024-01274-z

実験手法

X-RAY DIFFRACTION (2.57 Å)