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SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models

文献类型：期刊论文

作者Jiang, Xi-fei2; Dai, Yang3; Peng, Xia3; Shen, Yan-yan3; Su, Yi3; Wei, Man-man1,4; Liu, Wei-ren2; Ding, Zhen-bin2; Zhang, Ao3; Shi, Ying-hong2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2018-02
卷号39期号:2页码:243-250
关键词human cancer anticancer drug SOMCL-085 receptor tyrosine kinase FGFR xenograft nude mouse model
ISSN号1671-4083
DOI10.1038/aps.2017.96
文献子类Article
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 IC50 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 PLC. 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 G1/S phase. In the FGFR1-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.
WOS关键词ENDOTHELIAL GROWTH-FACTOR ; CELL LUNG-CANCER ; TYROSINE KINASE INHIBITOR ; FACTOR RECEPTOR ; TARGETED THERAPY ; RESISTANCE ; AMPLIFICATION ; ANGIOGENESIS ; MANAGEMENT ; DISCOVERY
资助项目National Natural Science Foundation of China[81473243] ; Science and Technology Commission of Shanghai Municipality[17431902900] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6163690
WOS记录号WOS:000423868000010
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/279936]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Shi, Ying-hong; Ai, Jing
作者单位1.Chinese Acad Sci, SOMCL, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Fudan Univ, Dept Liver Surg, Liver Canc Inst,Minist Educ, Zhongshan Hosp,Key Lab Carcinogenesis & Canc Inva, Shanghai 200032, Peoples R China;
3.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Jiang, Xi-fei,Dai, Yang,Peng, Xia,et al. SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models[J]. ACTA PHARMACOLOGICA SINICA,2018,39(2):243-250.
APA Jiang, Xi-fei.,Dai, Yang.,Peng, Xia.,Shen, Yan-yan.,Su, Yi.,...&Ai, Jing.(2018).SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models.ACTA PHARMACOLOGICA SINICA,39(2),243-250.
MLA Jiang, Xi-fei,et al."SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models".ACTA PHARMACOLOGICA SINICA 39.2(2018):243-250.

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来源：上海药物研究所

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