3 research outputs found
Structure-Based Design and Evaluation of Naphthalene Diimide G‑Quadruplex Ligands As Telomere Targeting Agents in Pancreatic Cancer Cells
Tetra-substituted
naphthalene diimide (ND) derivatives with positively
charged termini are potent stabilizers of human telomeric and gene
promoter DNA quadruplexes and inhibit the growth of human cancer cells
in vitro and in vivo. The present study reports the enhancement of
the pharmacological properties of earlier ND compounds using structure-based
design. Crystal structures of three complexes with human telomeric
intramolecular quadruplexes demonstrate that two of the four strongly
basic <i>N</i>-methyl-piperazine groups can be replaced
by less basic morpholine groups with no loss of intermolecular interactions
in the grooves of the quadruplex. The new compounds retain high affinity
to human telomeric quadruplex DNA but are 10-fold more potent against
the MIA PaCa-2 pancreatic cancer cell line, with IC<sub>50</sub> values
of ∼10 nM. The lead compound induces cellular senescence but
does not inhibit telomerase activity at the nanomolar dosage levels
required for inhibition of cellular proliferation. Gene array qPCR
analysis of MIA PaCa-2 cells treated with the lead compound revealed
significant dose-dependent modulation of a distinct subset of genes,
including strong induction of DNA damage responsive genes CDKN1A,
DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere
maintenance, including hPOT1 and PARP1
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(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