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.

Highlights

  • Pancreatic cancer remains one of the most difficult to treat human cancers.[1]

  • We have previously disclosed several focused libraries of naphthalene diimides, in particular, tetra-substituted analogues30,31,32a,33 (Figure 1a) with molecular design based on crystallographic data for a series of G4−ligand complexes.32a We report here on a new lead compound, 2,7-bis(3morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (CM03, 633.34 Da; compound 4 in Scheme 1 and Figure 1c), which contains two side chains terminating in morpholino groups, a third side chain terminating in a protonated pyrrolidino group, and a lower molecular weight compared to the parent tetrasubstituted compound MM4132a (831.08 Da; Figure 1a)

  • While pancreatic ductal adenocarcinoma (PDAC) is predominantly (>95%) driven by oncogenic KRAS,[40] the development of more targeted therapies against KRAS and other core PDAC associated pro-survival pathways including: Ras-Raf-MEK-ERK and PI3K-AKt-mTOR have proved futile owing to the highly mutagenic nature of the disease[5−8] and the ability of PDAC cells to rapidly switch between phenotypic states, resulting in the evasion of therapy.[47]

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Summary

Introduction

Pancreatic cancer remains one of the most difficult to treat human cancers.[1]. Pancreatic ductal adenocarcinomas (PDACs) comprise some 85% of diagnosed cases and are classified into several subtypes on the basis of expression analysis of major mutated genes.[2].

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