Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

中文翻译：

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雄激素受体依赖性染色质簇的小分子破坏


复发期间持续的雄激素受体 （AR） 信号传导是转移性去势抵抗性前列腺癌 （mCRPC） 的核心驱动因素。目前的 AR 拮抗剂，如恩杂鲁胺，未能为 AR 表达急剧增加的 mCRPC 患者提供长期益处。在这里，我们报告了在 AR 过表达模型中具有疗效的 AR 拮抗剂。这些分子与 AR 的配体结合结构域结合，促进 AR 定位到细胞核，同时有效且选择性地下调 AR 靶基因。在 mCRPC 模型中，分子 BG-15a 和药代动力学优化的 BG-15n 在体外和体内引起细胞和肿瘤生长的减少。BG-15a/n 处理导致 AR 驱动的表观基因组中关键基因的增强子和启动子之间的染色质环崩溃。启动子中的 AR 结合以及 3D 染色质聚集是基因响应所必需的。BG-15a/n 代表了治疗复发性 AR 驱动的 mCRPC 肿瘤患者的有前途的药物。