Androgen receptor condensates as drug targets

Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors' activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent. Overall design: Comparative gene expression profiling analysis of RNA-seq data for AR V7, AR V7 22YtoS and AR V7 22YtoF in PC3 cells.

转录因子（Transcription factors）是最具吸引力的治疗靶点之一，但长期以来被认为在很大程度上不可成药。本研究提供证据表明，小分子介导的致癌转录因子雄激素受体（androgen receptor）向相分离凝聚体（phase-separated condensates）的分区富集，在前列腺癌中具有治疗效应。我们证实，雄激素受体的相分离能力由其固有无序激活结构域（intrinsically disordered activation domain）中的芳香族残基与短不稳定螺旋所驱动。基于上述发现，我们开发了一类工具化合物，可将芳香基团共价结合至受体激活结构域内的半胱氨酸残基上。该类化合物可促进受体向凝聚体的分区富集，加速受体降解，抑制雄激素受体依赖的转录程序，并在前列腺癌小鼠模型与去势抵抗性前列腺癌（castration resistant prostate cancer）模型中展现出抗肿瘤发生效应。本研究结果确立了一个可推广的研究框架，可通过治疗性靶向致癌转录因子及其他疾病相关蛋白的固有无序区域（intrinsically disordered regions）的相分离能力实现治疗目的。
实验设计：对PC3细胞中AR V7、AR V7 22YtoS及AR V7 22YtoF的RNA测序（RNA-seq）数据进行比较基因表达谱分析。