Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences ; Guangzhou Medical University, Guangzhou 510530 , China.
University of Chinese Academy of Sciences , No. 19 Yuquan Road , Beijing 100049 , China.
J Med Chem. 2019 May 9;62(9):4716-4730. doi: 10.1021/acs.jmedchem.9b00327. Epub 2019 Apr 22.
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 IC 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.
我们报告了核受体 RORγ 反向激动剂的设计、优化和生物学评估，作为治疗前列腺癌的治疗剂。最有效的化合物 27（命名为 XY101）在基于细胞的报告基因测定中具有细胞活性，IC 值为 30 nM，对其他核受体亚型具有良好的选择性。27 与 RORγ 配体结合域的共晶结构为其拮抗机制提供了坚实的结构基础。27 强烈抑制细胞生长、集落形成以及 AR、AR-V7 和 PSA 的表达。27 还表现出良好的代谢稳定性和药代动力学特征，口服生物利用度为 59%，半衰期为 7.3 h。值得注意的是，27 在小鼠前列腺癌异种移植模型中表现出有希望的治疗效果，显著抑制肿瘤生长。这种有效、选择性、代谢稳定且可口服的 RORγ 反向激动剂代表了一类新的化合物，有望成为治疗前列腺癌的潜在疗法。
