Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

中文翻译：

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Metarrestin是一种核仁区隔抑制剂，可有效抑制转移。

由于缺乏针对这种复杂过程的特异性抑制剂，转移仍然是癌症死亡的主要原因。为了鉴定选择性靶向转移状态的化合物，我们使用核仁区室（PNC）（一种与癌细胞的转移行为相关的复杂核结构）作为表型标记，可对14万种结构多样的化合物进行高含量筛选。通过优化筛选命中获得的美瑞斯汀可以分解多种癌细胞系中的PNC，在体外抑制入侵，抑制三种人类癌症小鼠模型的转移发展，并在无器官毒性的转移性胰腺癌异种移植模型中延长小鼠的存活期或明显的不良影响。Metarrestin会破坏核仁结构并抑制RNA聚合酶（Pol）I的转录，至少部分地通过与翻译延伸因子eEF1A2相互作用来实现。因此，金属抑制蛋白代表了治疗转移性癌症的潜在治疗方法。