Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis.
Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis.
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吡咯并嘧啶衍生物的发现和优化，作为核仁周围室的选择性干扰剂，核仁周围室是肿瘤进展到转移的标志。
DOI：
10.1021/acs.jmedchem.2c00204
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发表时间：
2022-06-23
影响因子：
7.3
通讯作者：
Marugan, Juan J.
中科院分区：
文献类型：
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作者：
Frankowski, Kevin J.;Patnaik, Samarjit;Wang, Chen;Southall, Noel;Dutta, Dipannita;De, Soumitta;Li, Dandan;Dextras, Christopher;Lin, Yi-Han;Bryant-Connah, Marthe;Davis, Danielle;Wang, Feijun;Wachsmuth, Leah M.;Shah, Pranav;Williams, Jordan;Kabir, Md;Zhu, Edward;Baljinnyam, Bolormaa;Wang, Amy;Xu, Xin;Norton, John;Ferrer, Marc;Titus, Steve;Simeonov, Anton;Zheng, Wei;Griner, Lesley A. Mathews;Jadhav, Ajit;Aube, Jeffrey;Henderson, Mark J.;Rudloff, Udo;Schoenen, Frank J.;Huang, Sui;Marugan, Juan J.
核周区室 (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可选择性降低癌细胞中 PNC 患病率的新型小分子。我们鉴定并进一步优化了吡咯并嘧啶系列，能够在亚微摩尔浓度下降低 PC3M 癌细胞中 PNC 的患病率，而不影响细胞活力。对活性所需结构元素的 SAR 探索发现了几种有效的化合物。对体外药物特性的分析导致了生物可利用的类似物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生存率，目前正在一项首次人体一期临床试验中进行评估。
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. SAR 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.
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影响因子：
8.6
作者：
Shah, Pranav;Siramshetty, Vishal Babu;Dac-Trung Nguyen
通讯作者：
Dac-Trung Nguyen
影响因子：
2.5
作者：
Hoon, Dave S. B.;Ferris, Robert;Pantel, Klaus
通讯作者：
Pantel, Klaus
影响因子：
2.6
作者：
Costanzo, Erin S.;Sood, Anil K.;Lutgendorf, Susan K.
通讯作者：
Lutgendorf, Susan K.
影响因子：
--
作者：
Norton, John T.;Titus, Steven A.;Huang, Sui
通讯作者：
Huang, Sui
DOI：
10.1101/sqb.2010.75.026
发表时间：
2010
期刊：
Cold Spring Harbor symposia on quantitative biology
影响因子：
--
作者：
Slusarczyk A;Kamath R;Wang C;Anchel D;Pollock C;Lewandowska MA;Fitzpatrick T;Bazett-Jones DP;Huang S
通讯作者：
Huang S