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

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.