Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule

Research output: Contribution to journalArticlepeer-review

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Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule. / Marchetti, C; Zyner, KG; Ohnmacht, SA; Robson, M; Haider, SM; Morton, JP; Marsico, G; Vo, T; Laughlin-Toth, S; Ahmed, AA; Di, Vita G; Pazitna, I; Gunaratnam, M; Besser, RJ; Andrade, ACG; Diocou, S; Pike, Jeremy; Tannahill, D; Pedley, RB; Evans, TRJ; Wilson, WD; Balasubramanian, S; Neidle, S.

In: Journal of Medicinal Chemistry, Vol. 61, No. 6, 22.03.2018, p. 2500-2517.

Research output: Contribution to journalArticlepeer-review

Harvard

Marchetti, C, Zyner, KG, Ohnmacht, SA, Robson, M, Haider, SM, Morton, JP, Marsico, G, Vo, T, Laughlin-Toth, S, Ahmed, AA, Di, VG, Pazitna, I, Gunaratnam, M, Besser, RJ, Andrade, ACG, Diocou, S, Pike, J, Tannahill, D, Pedley, RB, Evans, TRJ, Wilson, WD, Balasubramanian, S & Neidle, S 2018, 'Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule', Journal of Medicinal Chemistry, vol. 61, no. 6, pp. 2500-2517. https://doi.org/10.1021/acs.jmedchem.7b01781

APA

Marchetti, C., Zyner, KG., Ohnmacht, SA., Robson, M., Haider, SM., Morton, JP., Marsico, G., Vo, T., Laughlin-Toth, S., Ahmed, AA., Di, V. G., Pazitna, I., Gunaratnam, M., Besser, RJ., Andrade, ACG., Diocou, S., Pike, J., Tannahill, D., Pedley, RB., ... Neidle, S. (2018). Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule. Journal of Medicinal Chemistry, 61(6), 2500-2517. https://doi.org/10.1021/acs.jmedchem.7b01781

Vancouver

Author

Marchetti, C ; Zyner, KG ; Ohnmacht, SA ; Robson, M ; Haider, SM ; Morton, JP ; Marsico, G ; Vo, T ; Laughlin-Toth, S ; Ahmed, AA ; Di, Vita G ; Pazitna, I ; Gunaratnam, M ; Besser, RJ ; Andrade, ACG ; Diocou, S ; Pike, Jeremy ; Tannahill, D ; Pedley, RB ; Evans, TRJ ; Wilson, WD ; Balasubramanian, S ; Neidle, S. / Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 6. pp. 2500-2517.

Bibtex

@article{0c9fbf03ce4740a09857cb504e4850ac,
title = "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.",
author = "C Marchetti and KG Zyner and SA Ohnmacht and M Robson and SM Haider and JP Morton and G Marsico and T Vo and S Laughlin-Toth and AA Ahmed and Di, {Vita G} and I Pazitna and M Gunaratnam and RJ Besser and ACG Andrade and S Diocou and Jeremy Pike and D Tannahill and RB Pedley and TRJ Evans and WD Wilson and S Balasubramanian and S Neidle",
year = "2018",
month = mar,
day = "22",
doi = "10.1021/acs.jmedchem.7b01781",
language = "English",
volume = "61",
pages = "2500--2517",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "6",

}

RIS

TY - JOUR

T1 - Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule

AU - Marchetti, C

AU - Zyner, KG

AU - Ohnmacht, SA

AU - Robson, M

AU - Haider, SM

AU - Morton, JP

AU - Marsico, G

AU - Vo, T

AU - Laughlin-Toth, S

AU - Ahmed, AA

AU - Di, Vita G

AU - Pazitna, I

AU - Gunaratnam, M

AU - Besser, RJ

AU - Andrade, ACG

AU - Diocou, S

AU - Pike, Jeremy

AU - Tannahill, D

AU - Pedley, RB

AU - Evans, TRJ

AU - Wilson, WD

AU - Balasubramanian, S

AU - Neidle, S

PY - 2018/3/22

Y1 - 2018/3/22

N2 - 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.

AB - 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.

UR - http://europepmc.org/abstract/med/29356532

U2 - 10.1021/acs.jmedchem.7b01781

DO - 10.1021/acs.jmedchem.7b01781

M3 - Article

C2 - 29356532

VL - 61

SP - 2500

EP - 2517

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -