OBJECTIVE The bromodomain and extra-terminal (BET) family of proteins provides a scaffolding platform for the recruitment and tethering of transcription factors to acetylated chromatin, thereby modulating gene expression. In this study, we evaluated the efficacy of the BET-inhibitor PFI-1 to diminish AR/AR-V7 signaling and proliferation in castration-resistant prostate cancer cells. METHODS Prostate-specific antigen and androgen receptor (AR) protein were quantified by means of two commercial ELISAs. Transactivation of the AR, AR-V7 and Q641X was determined by reporter gene assays. Cell proliferation was measured using a colorimetric MTT-assay. RESULTS PFI-1 dose-dependently inhibited transactivation of full-length AR (non- mutated, i.e., wild-type or point-mutated/promiscuous forms) without affecting their cellular protein levels. Moreover, PFI-1 was active against C-terminally truncated constitutively active ARs like AR-V7 and Q641X. Prostate cancer cells exhibiting a transcriptionally active AR-signaling complex (LNCaP, 22Rv1) were more susceptible to the growth-inhibitory effects than the AR-negative PC-3 cells. CONCLUSION The quinazolinone PFI-1 is a highly efficient inhibitor of AR-signaling-competent prostate cancer cells in vitro. PFI-1 could serve as a lead compound for the development of new therapeutics able to block AR/AR-V7 signaling in advanced prostate cancer.

中文翻译：

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BET 抑制剂 PFI-1 减少前列腺癌细胞中的 AR/AR-V7 信号。

目的 溴结构域和末端 (BET) 蛋白家族为转录因子募集和连接至乙酰化染色质提供了支架平台，从而调节基因表达。在这项研究中，我们评估了 BET 抑制剂 PFI-1 减少 AR/AR-V7 信号传导和去势抵抗前列腺癌细胞增殖的功效。方法 前列腺特异性抗原和雄激素受体 (AR) 蛋白通过两种商业 ELISA 进行定量。AR、AR-V7 和 Q641X 的反式激活通过报告基因分析确定。使用比色MTT测定法测量细胞增殖。结果 PFI-1 剂量依赖性地抑制全长 AR（非突变，即野生型或点突变/混杂形式）的反式激活，而不影响它们的细胞蛋白质水平。而且，PFI-1 对 C 端截短的组成型活性 AR，如 AR-V7 和 Q641X 具有活性。表现出转录活性 AR 信号复合物（LNCaP，22Rv1）的前列腺癌细胞比 AR 阴性 PC-3 细胞更容易受到生长抑制作用的影响。结论 喹唑啉酮 PFI-1 是一种高效的体外 AR 信号传导前列腺癌细胞抑制剂。PFI-1 可以作为一种先导化合物，用于开发能够阻断晚期前列腺癌中 AR/AR-V7 信号传导的新疗法。结论 喹唑啉酮 PFI-1 是一种高效的体外 AR 信号传导前列腺癌细胞抑制剂。PFI-1 可以作为一种先导化合物，用于开发能够阻断晚期前列腺癌中 AR/AR-V7 信号传导的新疗法。结论 喹唑啉酮 PFI-1 是一种高效的体外 AR 信号传导前列腺癌细胞抑制剂。PFI-1 可以作为一种先导化合物，用于开发能够阻断晚期前列腺癌中 AR/AR-V7 信号传导的新疗法。