Abstract
We report the design, optimization, and biological evaluation of nuclear receptor RORγinverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC 50 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 RORγligand 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 RORγinverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4716-4730 |
| Number of pages | 15 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 9 2019 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer. / 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, Hongwu; Xu, Jinxin; Xu, Yong.
In: Journal of Medicinal Chemistry, Vol. 62, No. 9, 09.05.2019, p. 4716-4730.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer
AU - Zhang, Yan
AU - Wu, Xishan
AU - Xue, Xiaoqian
AU - Li, Chenchang
AU - Wang, Junjian
AU - Wang, Rui
AU - Zhang, Cheng
AU - Wang, Chao
AU - Shi, Yudan
AU - Zou, Lingjiao
AU - Li, Qiu
AU - Huang, Zenghong
AU - Hao, Xiaojuan
AU - Loomes, Kerry
AU - Wu, Donghai
AU - Chen, Hongwu
AU - Xu, Jinxin
AU - Xu, Yong
PY - 2019/5/9
Y1 - 2019/5/9
N2 - We report the design, optimization, and biological evaluation of nuclear receptor RORγinverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC 50 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 RORγligand 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 RORγinverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.
AB - We report the design, optimization, and biological evaluation of nuclear receptor RORγinverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC 50 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 RORγligand 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 RORγinverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.
UR - http://www.scopus.com/inward/record.url?scp=85065097560&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065097560&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b00327
DO - 10.1021/acs.jmedchem.9b00327
M3 - Article
C2 - 30964293
AN - SCOPUS:85065097560
VL - 62
SP - 4716
EP - 4730
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -