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

9 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγInverse Agonist for Treatment of Castration-Resistant Prostate Cancer'. Together they form a unique fingerprint.

  • Cite this

    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, 62(9), 4716-4730. https://doi.org/10.1021/acs.jmedchem.9b00327