A Selective ERRα/γ Inverse Agonist, SLU-PP-1072, Inhibits the Warburg Effect and Induces Apoptosis in Prostate Cancer Cells.,ACS Chemical Biology

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A Selective ERRα/γ Inverse Agonist, SLU-PP-1072, Inhibits the Warburg Effect and Induces Apoptosis in Prostate Cancer Cells.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-09-08 , DOI: 10.1021/acschembio.0c00670
Emmalie Schoepke _{1,

2} , Cyrielle Billon ₂ , Keith M Haynes ₁ , Amer Avdagic ₁ , Sadichha Sitaula ₁ , Ryan Sanders ₂ , Christiana M Adeyemi ₁ , John K Walker _{1,

3} , Thomas P Burris _{2,

3}

Affiliation

The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ.

中文翻译：

选择性 ERRα/γ 反向激动剂 SLU-PP-1072 可抑制 Warburg 效应并诱导前列腺癌细胞凋亡。

雌激素相关受体 (ERR) 是核受体的一个亚组，在细胞代谢调节中发挥作用。前列腺癌 (PCa) 细胞表现出改变的代谢特征，例如 Warburg 效应，并且 ERR 与驱动这种表型有关。尽管缺乏已知的内源配体，但已经发现了针对 ERR 的合成配体。例如，ERRα 反向激动剂 XCT790 调节 PCa 细胞中的代谢途径，但它也可以作为独立于 ERRα 靶向的线粒体解偶联剂发挥作用。在这里，我们描述了一种新型双重 ERRα/γ 反向激动剂 SLU-PP-1072，它源自 GSK4716 ERRγ 激动剂支架，与 XCT790 支架不同。 SLU-PP-1072 改变 PCa 细胞代谢和基因表达，导致细胞周期失调和细胞凋亡增加，但没有急性线粒体解偶联活性。我们的数据表明，抑制 ERRα/γ 可能有益于 PCa 的治疗，而 SLU-PP-1072 提供了一种独特的化学工具来评估 ERRα 和 ERRγ 的药理学。

更新日期：2020-09-20

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