Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G‑Quadruplex-Binding Small Molecule

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(2H,7H)-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.

人类胰腺导管腺癌（PDAC）的发生与多条信号通路的失调密切相关。本研究报道了一种治疗PDAC的全新策略：通过靶向PDAC通路中G四链体（G-quadruplexes）富集的癌症相关基因，使用三取代萘二酰亚胺类G四链体结合化合物2,7-双(3-吗啉代丙基)-4-((2-(1-吡咯烷基)乙基)氨基)苯并[lmn][3,8]菲咯啉-1,3,6,8(2H,7H)-四酮（CM03）。该化合物通过计算机建模设计而成，可强效抑制PDAC细胞系的细胞增殖，并在PDAC模型中展现出抗癌活性，其疗效优于临床常用治疗药物吉西他滨。本研究采用全转录组RNA测序（RNA-seq）技术，分析了该G四链体结合小分子对全局基因表达的影响。分析结果显示，大量富含潜在G四链体元件、且参与PDAC生存、转移及耐药关键通路的基因均被下调。CM03诱导的基因表达变化代表了针对人类PDAC复杂性的全局应答，或可推广应用于其他当前难以治疗的癌症类型。