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

Abstract

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.

G-quadruplexes sequester free heme in living cells

“…Hierarchical cluster analysis of log 2 (Fold Change) of these genes in all of the four publicly available datasets documenting the effects of G4 ligands on gene expression supported the view that NRF2-regulated genes are key targets of hemin, PhenDC3, and the anthraquinone derivative ( Figure S5D ). In contrast, a computer-designed G4 ligand of distinct structure, the trisubstituted naphthalene diimide derivative, CM03 ( Figure S5A ), which is a potent inhibitor of proliferation of pancreatic tumor cell lines and xenografts [Marchetti C et al 2018], did not affect expression of these four genes.…”

The Structure and Function of DNA G-Quadruplexes

“…Since then, a variety of different G4-targeted ligands have been described to modulate the expression of genes carrying a sequence capable of forming a G4 in their respective promoters. So far, few studies have investigated transcriptional changes on a genome-wide level [29]. More carefully designed controls will be needed to assess whether a particular G4 is in fact the main biological target or if changes in target gene expression are a result of the ligand binding to other genomic (G4 or non-G4) targets.…”

Therapeutic strategies for targeting telomerase in cancer

“…Extending the acridine core to a wider hydrophobic core while retaining the two diimine side arms yielded a range of perylene derivatives and substituted naphthalene diimides ( 63 ); among them, PIPER ( 64 ) is a representative compound that shows an inhibitory effect of IC 50 ‐TRAP = 20 μM compared to Braco‐19 . PIPER has a free (pH 7) state and an aggregated state (pH 8.5) .…”