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

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.本研究报道了用于前列腺癌治疗的核受体RORγ（nuclear receptor RORγ）反向激动剂的设计、优化及生物学评价。活性最强的化合物27（命名为XY101）在基于细胞的报告基因实验中展现出30 nM的半数抑制浓度（IC50），且对其他核受体亚型具有良好的选择性。化合物27与RORγ配体结合域形成复合物的共晶结构，为其拮抗作用机制提供了坚实的结构基础。该化合物可有效抑制细胞增殖、集落形成，以及雄激素受体（Androgen Receptor, AR）、AR-V7和前列腺特异性抗原（Prostate-Specific Antigen, PSA）的表达。同时，化合物27展现出良好的代谢稳定性与药代动力学特性：口服生物利用度达59%，半衰期为7.3小时。值得注意的是，在小鼠前列腺癌异种移植模型中，化合物27展现出极具潜力的治疗效果，可显著抑制肿瘤生长。这类强效、高选择性、代谢稳定且可口服的RORγ反向激动剂，代表了一类全新的潜在前列腺癌治疗候选化合物。