当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-07 , DOI: 10.1021/acs.jmedchem.7b01781 Chiara Marchetti 1 , Katherine G Zyner 2 , Stephan A Ohnmacht 1 , Mathew Robson 3 , Shozeb M Haider 1 , Jennifer P Morton 4, 5 , Giovanni Marsico 2 , Tam Vo 6 , Sarah Laughlin-Toth 6 , Ahmed A Ahmed 1 , Gloria Di Vita 1 , Ingrida Pazitna 1 , Mekala Gunaratnam 1 , Rachael J Besser 1 , Ana C G Andrade 1 , Seckou Diocou 7 , Jeremy A Pike 2 , David Tannahill 2 , R Barbara Pedley 7 , T R Jeffry Evans 4, 5 , W David Wilson 6 , Shankar Balasubramanian 2, 8, 9 , Stephen Neidle 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-07 , DOI: 10.1021/acs.jmedchem.7b01781 Chiara Marchetti 1 , Katherine G Zyner 2 , Stephan A Ohnmacht 1 , Mathew Robson 3 , Shozeb M Haider 1 , Jennifer P Morton 4, 5 , Giovanni Marsico 2 , Tam Vo 6 , Sarah Laughlin-Toth 6 , Ahmed A Ahmed 1 , Gloria Di Vita 1 , Ingrida Pazitna 1 , Mekala Gunaratnam 1 , Rachael J Besser 1 , Ana C G Andrade 1 , Seckou Diocou 7 , Jeremy A Pike 2 , David Tannahill 2 , R Barbara Pedley 7 , T R Jeffry Evans 4, 5 , W David Wilson 6 , Shankar Balasubramanian 2, 8, 9 , Stephen Neidle 1
Affiliation
|
Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[ lmn][3,8]phenanthroline-1,3,6,8(2 H,7 H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.
中文翻译：
使用 G-四联体结合小分子靶向胰腺导管腺癌中的多个效应器通路。
人胰腺导管腺癌（PDAC）涉及多种信号通路的失调。描述了一种治疗 PDAC 的新方法，涉及使用三取代萘二酰亚胺四联体结合化合物 2,7-双(3-吗啉代丙基)-4 靶向 PDAC 通路中具有过度表达的 G-四联体的癌症基因-((2-(吡咯烷-1-基)乙基)氨基)苯并[1mn][3,8]菲咯啉-1,3,6,8(2H,7H)-四酮(CM03)。该化合物是通过计算机建模设计的，是 PDAC 细胞系中细胞生长的有效抑制剂，并且在 PDAC 模型中具有抗癌活性，与常用疗法吉西他滨相比具有优越的特性。全转录组 RNA-seq 方法已用于分析这种四链体结合小分子对整体基因表达的影响。这揭示了大量基因的下调，这些基因富含假定的四链体元件，并参与 PDAC 存活、转移和耐药性的重要途径。 CM03 产生的变化代表了对人类 PDAC 复杂性的全球反应，并且可能适用于其他目前难以治疗的癌症。
更新日期：2018-01-22
中文翻译：
使用 G-四联体结合小分子靶向胰腺导管腺癌中的多个效应器通路。
人胰腺导管腺癌（PDAC）涉及多种信号通路的失调。描述了一种治疗 PDAC 的新方法，涉及使用三取代萘二酰亚胺四联体结合化合物 2,7-双(3-吗啉代丙基)-4 靶向 PDAC 通路中具有过度表达的 G-四联体的癌症基因-((2-(吡咯烷-1-基)乙基)氨基)苯并[1mn][3,8]菲咯啉-1,3,6,8(2H,7H)-四酮(CM03)。该化合物是通过计算机建模设计的，是 PDAC 细胞系中细胞生长的有效抑制剂，并且在 PDAC 模型中具有抗癌活性，与常用疗法吉西他滨相比具有优越的特性。全转录组 RNA-seq 方法已用于分析这种四链体结合小分子对整体基因表达的影响。这揭示了大量基因的下调，这些基因富含假定的四链体元件，并参与 PDAC 存活、转移和耐药性的重要途径。 CM03 产生的变化代表了对人类 PDAC 复杂性的全球反应，并且可能适用于其他目前难以治疗的癌症。
京公网安备 11010802027423号