Oncotarget

Research Papers:

The pyrazolyl-urea GeGe3 inhibits tumor angiogenesis and reveals dystrophia myotonica protein kinase (DMPK)1 as a novel angiogenesis target

Elda Meta, Beat A. Imhof, Patricia Ropraz, Richard J. Fish, Chiara Brullo, Olga Bruno and Adama Sidibé _

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Oncotarget. 2017; 8:108195-108212. https://doi.org/10.18632/oncotarget.22598

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Abstract

Elda Meta1, Beat A. Imhof2, Patricia Ropraz2, Richard J. Fish3, Chiara Brullo1, Olga Bruno1 and Adama Sidibé2

1Department of Pharmacy, Medicinal Chemistry Section, University of Genoa, 16132 Genoa, Italy

2Department of Pathology and Immunology, University of Geneva, 1211 Genève, Switzerland

3Department of Genetic Medicine and Development, University of Geneva, 1211 Genève, Switzerland

Correspondence to:

Adama Sidibé, email: adama.sidibe@unige.ch

Keywords: angiogenesis; novel target; pyrazolyl-urea; kinase inhibitors; DMPK

Received: May 04, 2017     Accepted: July 26, 2017     Published: November 21, 2017

ABSTRACT

The limitation of targeting VEGF/VEGFR2 signalling to stop angiogenesis in cancer therapy has been blamed on re-activation of alternative receptor tyrosine kinases by compensatory angiogenic factors. Targeting MAPK and PI3K signaling pathways in endothelial cells may be an alternative or complementary approach. Herein we aimed to evaluate the antitumor and antiangiogenic potential of a novel pyrazolyl-urea kinase inhibitor, GeGe3, and to identify its kinase targets.

We found GeGe3 to inhibit the proliferation of HUVEC and endothelial tube formation. GeGe3 impaired inter-segmental angiogenesis during development of zebrafish embryos. In mice, GeGe3 blocked angiogenesis and tumor growth in transplanted subcutaneous Lewis Lung Carcinomas. Screening for GeGe3-targeted kinases revealed Aurora B, Aurora C, NEK10, polo-like kinase (PLK)2, PLK3, DMPK1 and CAMK1 as candidate targets. Biochemical analysis of these kinases showed DMPK1 regulation upon VEGF challenge. Investigation of the role of DMPK1 in endothelial cells revealed DMPK1 as a novel mediator of angiogenesis that controls the activation of MAPK signaling, proliferation and migration. GeGe3 alters angiogenesis by targeting DMPK in tumor endothelial cells and pericytes.

The pyrazolyl-urea GeGe3, a novel blocker of MAPK and PI3K pathways, strongly inhibits physiological and tumor angiogenesis. We also report GeGe3-targeted kinase DMPK as a novel mediator of angiogenesis.


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