Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable ROR gamma Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable ROR gamma Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer
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XY101 的发现和表征，一种有效的、选择性的、口服生物可利用的 ROR γ 反向激动剂，用于治疗去势抵抗性前列腺癌
DOI：
10.1021/acs.jmedchem.9b00327
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发表时间：
2019
影响因子：
7.3
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Zhang Yan;Wu Xishan;Xue Xiaoqian;Li Chenchang;Wang Junjian;Wang Rui;Zhang Cheng;Wang Chao;Shi Yudan;Zou Lingjiao;Li Qiu;Huang Zenghong;Hao Xiaojuan;Loomes Kerry;Wu Donghai;Chen Hong Wu;Xu Jinxin;Xu Yong
We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound27(designated as XY101) exhibited cellular activity with an IC50value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of27in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism.27potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA.27also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably,27demonstrated 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.
