Meta Elda, Imhof Beat A, Ropraz Patricia, Fish Richard J, Brullo Chiara, Bruno Olga, Sidibé Adama
Department of Pharmacy, Medicinal Chemistry Section, University of Genoa, 16132 Genoa, Italy.
Department of Pathology and Immunology, University of Geneva, 1211 Genève, Switzerland.
Oncotarget. 2017 Nov 21;8(64):108195-108212. doi: 10.18632/oncotarget.22598. eCollection 2017 Dec 8.
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.
在癌症治疗中，靶向VEGF/VEGFR2信号通路以阻止血管生成的局限性被归咎于补偿性血管生成因子重新激活替代受体酪氨酸激酶。靶向内皮细胞中的MAPK和PI3K信号通路可能是一种替代或补充方法。在此，我们旨在评估一种新型吡唑基脲激酶抑制剂GeGe3的抗肿瘤和抗血管生成潜力，并确定其激酶靶点。我们发现GeGe3可抑制人脐静脉内皮细胞（HUVEC）的增殖和内皮管形成。GeGe3会损害斑马鱼胚胎发育过程中的节间血管生成。在小鼠中，GeGe3可阻断移植的皮下Lewis肺癌中的血管生成和肿瘤生长。对GeGe3靶向激酶的筛选显示，极光激酶B、极光激酶C、NEK10、polo样激酶（PLK）2、PLK3、DMPK1和钙调蛋白激酶1（CAMK1）为候选靶点。对这些激酶的生化分析表明，VEGF刺激可调节DMPK1。对DMPK1在内皮细胞中的作用研究表明，DMPK1是血管生成的一种新型介质，可控制MAPK信号的激活、细胞增殖和迁移。GeGe3通过靶向肿瘤内皮细胞和周细胞中的DMPK来改变血管生成。吡唑基脲GeGe3是一种新型的MAPK和PI3K通路阻滞剂，可强烈抑制生理性和肿瘤血管生成。我们还报告了GeGe3靶向激酶DMPK是血管生成的一种新型介质。
