somcl085anovelmultitargetedfgfrinhibitordisplayspotentanticanceractivityinfgfraddictedhumancancermodels

doi:10.1038/aps.2017.96

	somcl085anovelmultitargetedfgfrinhibitordisplayspotentanticanceractivityinfgfraddictedhumancancermodels
	Jiang Xifei 1; Dai Yang 2; Peng Xia 2; Shen Yanyan 2; Su Yi 2; Wei Manman 2; Liu Weiren 1; Ding Zhenbin 1; Zhang Ao 2; Shi Yinghong 1
刊名	actapharmacologicasinica
	2018
卷号	39 期号:2 页码:243
关键词	human cancer anticancer drug SOMCL-085 receptor tyrosine kinase FGFR xenograft nude mouse model
ISSN号	1671-4083
DOI	10.1038/aps.2017.96
英文摘要	Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC_(50) values of 1.8,1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR,but without obvious inhibitory effect on other 12 tyrosine kinases. In 3 representative human cancer cell lines with different mechanisms of FGFR activation tested, SOMCL-085 (20-500 nmol/L) dose-dependently inhibited FGFR1-3 phosphorylation and the phosphorylation of their key downstream effectors PLCγ and Erk. In 7 FGFR aberrant human cancer cell lines, regardless of the mechanistic complexity of FGFR over-activation, SOMCL-085 potently inhibited FGFR-driven cell proliferation by arresting cells at the G_1/S phase. In the FGFRl-amplified lung cancer cell line H1581 xenograft mice and FGFR2-amplified gastric cancer cell line SNU16 xenograft mice, oral administration of SOMCL-085 (25,50 mg.kg~(-1).d~(-1)) for 21 days substantially suppressed tumor growth without affecting their body-weight. These results suggest that SOMCL-085 is a potent multi-target FGFR inhibitor that inhibits the FGFR-dependent neoplastic phenotypes of human cancer cells in vitro and in vivo.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/285335]
专题	中国科学院上海药物研究所
作者单位	1.复旦大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Jiang Xifei,Dai Yang,Peng Xia,et al. somcl085anovelmultitargetedfgfrinhibitordisplayspotentanticanceractivityinfgfraddictedhumancancermodels[J]. actapharmacologicasinica,2018,39(2):243.
APA	Jiang Xifei.,Dai Yang.,Peng Xia.,Shen Yanyan.,Su Yi.,...&Al Jing.(2018).somcl085anovelmultitargetedfgfrinhibitordisplayspotentanticanceractivityinfgfraddictedhumancancermodels.actapharmacologicasinica,39(2),243.
MLA	Jiang Xifei,et al."somcl085anovelmultitargetedfgfrinhibitordisplayspotentanticanceractivityinfgfraddictedhumancancermodels".actapharmacologicasinica 39.2(2018):243.