KU Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, United States.
Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States.
The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure–activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of
in vitro
drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.
中文翻译：
核仁周室 (PNC) 是在核仁外围发现的动态亚核体。PNC 富含 RNA 转录物和 RNA 结合蛋白，反映了基因组组织的不同状态。PNC 患病率与癌症进展和转移能力呈正相关，使其成为转移性癌症进展的有用标志物。开发了一种高通量、高含量的检测方法来鉴定选择性降低癌细胞中 PNC 患病率的新型小分子。我们确定并进一步优化了吡咯并嘧啶系列，该系列能够在亚微摩尔浓度下降低 PC3M 癌细胞中的 PNC 患病率，而不会影响细胞活力。对活性所必需的结构元素的构效关系探索导致发现了几种有效的化合物。分析
体外
药物样特性导致了生物可利用类似物metarrestin的发现，该类似物在啮齿动物模型中显示出有效的抗转移活性并提高了存活率，目前正在首次人体1期临床试验中进行评估。
