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

该合作团队通过高通量筛选和化学优化，开发出一种名为甲氨脲素的化合物，它可以破坏不同类型癌细胞的核周腔室（PNC）。PNC是一种位于癌细胞细胞核内的结构，与转移能力有关。在多种癌症小鼠模型中，甲氨restin抑制了肿瘤的侵袭和转移，延长了动物的生存期，提示其与患者的潜在相关性。在此期间，使用各种靶点反卷积方法的广泛研究导致化合物作用机制的潜在靶点和途径的揭示。该团队继续使用一套体外和体内工具研究甲脲素的作用机制。为了避免脑渗透和潜在的神经毒性，通过结构-活性关系研究产生了新的类似物。这些努力也将有助于了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.