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

Abstract

We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 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 RORγ ligand 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 RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.

• Authors: 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, Hong-Wu Chen, Jinxin Xu, Yong Xu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 9 Pg. 4716-4730 (05 09 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30964293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Acetanilides
• Antineoplastic Agents
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Sulfonamides

Topics

• Acetanilides (chemical synthesis, metabolism, therapeutic use)
• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, therapeutic use)
• Binding Sites
• Cell Proliferation (drug effects)
• Drug Design
• Drug Inverse Agonism
• Gene Expression (drug effects)
• Male
• Mice
• Microsomes, Liver (metabolism)
• Molecular Docking Simulation
• Molecular Structure
• Nuclear Receptor Subfamily 1, Group F, Member 3 (agonists, chemistry, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Protein Binding
• Rats
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, metabolism, therapeutic use)
• Xenograft Model Antitumor Assays