Progression of Metarrestin that Reduces PNC Prevalence and Elucidation of its Mechanism of Action

这个合作团队通过高通量筛选，然后进行化学优化，开发出一种名为Metarrestin的化合物，它可以破坏不同类型癌细胞的核周间隔(PNC)。PNC是位于癌细胞核内的一种结构，与转移能力有关。Metarrestin抑制多种小鼠肿瘤模型的肿瘤侵袭和转移，并延长动物的生存时间，这表明它可能与患者的翻译相关。在此期间，利用各种靶标去卷积方法进行的广泛研究揭示了化合物作用机制的潜在靶标和途径。该团队继续使用一系列体外和体内工具研究Metarrestin的作用机制。新的类似物已经通过构效关系研究产生，目的是避免大脑渗透和潜在的神经毒性。这些努力也将有助于理解转移的复杂性质及其与PNC的关系。

The collaborative team, through high-throughput screening followed by chemical optimization, developed a compound, metarrestin, which disrupts the perinuclear compartment (PNC) in different types of cancer cells. The PNC is a structure located within the nuclei of cancer cells and associated with metastatic capacity. Metarrestin inhibited tumor invasion and metastasis in multiple mouse models of cancer and prolonged the animals survival, suggesting its potential relevance for translation to patients. During this period, extensive studies using a variety of target deconvolution approaches led to the uncovering of potential targets and pathways for the compounds mechanism of action. The team has continued to investigate the mechanism of action of metarrestin using a set of in vitro and in vivo tools. New analogues have been generated through structure-activity relationship studies with the aim of avoiding brain penetration and potential neurotoxicity. These efforts will also help understand the complex nature of metastasis and its relation to the PNC.