Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Yan Zhang, Xishan Wu, Xiaoqian Xue, Chenchang Li, Junjian Wang, Rui Wang, Cheng Zhang, Chao Wang, Yudan Shi, Lingjiao Zou, Qiu Li, Zenghong Huang, Xiaojuan Hao, Kerry Loomes, Donghai Wu, Hongwu Chen, Jinxin Xu, Yong Xu

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)4716-4730
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
DOIs
StatePublished - May 9 2019

Fingerprint

Castration
Prostatic Neoplasms
Cytoplasmic and Nuclear Receptors
Therapeutic Uses
Growth
Reporter Genes
Heterografts
Biological Availability
Half-Life
Pharmacokinetics
Therapeutics
Neoplasms

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 journalArticle

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, Xu, J & Xu, Y 2019, 'Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer', Journal of Medicinal Chemistry, vol. 62, no. 9, pp. 4716-4730. https://doi.org/10.1021/acs.jmedchem.9b00327
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. / Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 9. pp. 4716-4730.
@article{4c70244aa2e84b3b847f278b50bf93e0,
title = "Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer",
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.",
author = "Yan Zhang and Xishan Wu and Xiaoqian Xue and Chenchang Li and Junjian Wang and Rui Wang and Cheng Zhang and Chao Wang and Yudan Shi and Lingjiao Zou and Qiu Li and Zenghong Huang and Xiaojuan Hao and Kerry Loomes and Donghai Wu and Hongwu Chen and Jinxin Xu and Yong Xu",
year = "2019",
month = "5",
day = "9",
doi = "10.1021/acs.jmedchem.9b00327",
language = "English (US)",
volume = "62",
pages = "4716--4730",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "9",

}

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 -