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.