Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited ‘on-target’ toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment resistant prostate cancer cell lines and patient derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation since the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2 mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.

中文翻译：

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Thio-2 抑制去势抵抗性前列腺癌发生和进展所需的关键信号通路。

消除去势抵抗性前列腺癌（CRPC）中持续性雄激素受体（AR）信号传导的疗法仍然是一个未得到满足的临床需求。在 CRPC 中驱动转录活性的 AR N 端结构域 (NTD) 仍然是一个具有挑战性的治疗靶点。在此，我们证明 BAG-1 mRNA 高度表达，并与信号通路（包括 AR 信号通路）相关，这些信号通路与 CRPC 的发生和进展有关。此外，对 BAG-1 同工型 BAG 结构域的几何和物理化学特性的研究表明，它是一个易于处理但具有挑战性的药物靶点。此外，通过 BAG-1 亚型小鼠敲除研究，我们确认 BAG-1 亚型调节激素生理学，并且针对 BAG 结构域的疗法将与有限的“靶向”毒性相关。重要的是，假定的 BAG-1 亚型抑制剂 Thio-2 可抑制 AR 信号传导和与 CRPC 发生和进展有关的其他重要途径，从而减少治疗耐药性前列腺癌细胞系和患者衍生模型的生长。然而，Thio-2 引发观察到的表型的机制需要进一步阐明，因为 BAG-1 亚型的基因组废除无法重现 Thio-2 介导的表型。总体而言，这些数据支持对具有改善的类药特性的相关化合物作为 CRPC 的新型治疗方法进行质疑，并进一步强调了目前正在 CRPC 中进行临床评估的阻断持续 AR 信号传导的治疗的临床潜力。