Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer

doi:10.1186/s12885-015-1307-9

科研成果详情

题名	Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer
作者	Wu, Jianzhang1; Wei, Tao1; Tang, Qinqin1; Weng, Bixia1; Li, Wulan2; Jiang, Xin 1; Ding, Ting 3; Li, Xiaokun1; Liang, Guang1; Cai, Yuepiao1; Ji, Jiansong 1,4
发表日期	2015-04-12
发表期刊	BMC CANCER 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Fibroblast growth factor receptor 1 Non-small-cell lung cancer Non-ATP competitive FGFR1 inhibitors NDGA Anti-cancer
其他关键词	GROWTH-FACTOR-RECEPTOR ; TYROSINE-KINASE INHIBITORS ; MULTIPLE-MYELOMA CELLS ; DERIVATIVES ; RESISTANCE ; GEFITINIB ; MUTANT ; AGENTS ; NSCLC
摘要	Background: Fibroblast growth factor receptor 1 (FGFR1) is correlated closely with the occurrence and development of lung cancer. FGFR1 kinase inhibitors have exhibited significant therapeutic effects against non-small-cell lung cancer. Recently, non-ATP competitive FGFR1 inhibitors have attracted extensive attention due to their low side effects. Methods: Caliper Mobility Shift Assay was used for FGFR1 inhibition test and kinase inhibitory mode study. Hoechst staining and Annexin V/PI staining were used to evaluate the cell apoptosis induction. Western blot were then performed to confirm the intracellular FGFR1 inhibition and apoptotic protein expression. Finally, the anti-tumor effect and mechanism of Af23 and Ad23 was evaluated in vivo. Results: In this study, we designed, synthesized and discovered two novel non-ATP competitive FGFR1 inhibitors, Af23 and Ad23, using NDGA as a leading compound. They had IC50 values of 0.6 mu M and 1.4 mu M against FGFR1 kinase, respectively. The kinase inhibitory assay carried at different ATP concentrations showed that the FGFR1 inhibition mode of both Ad23 and Af23 was non-ATP-competitive. Further, Af23 and Ad23 significantly suppressed FGFR1 phosphorylation and cell proliferation in non-small-cell lung cancer (NSLCLC) H460 cells and induced cell apoptosis. Af23 and Ad23 also showed significant anti-tumor activity in the H460 xenograft mouse model, accompanied with the inhibition of FGFR1, ERK, and AKT phosphorylation without exhibiting toxicity. Conclusions: These results indicate that Ad23 and Af23 are potential agents for the treatment of non-small-cell lung cancer. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81173083, 81272462, 81473242]; Natural Science Funding of Zhejiang Province [LY13H160022, LY12H16003, LY12H30005]; Key Science Funding of Zhejiang Department of Health [WKJ2013-2-021]; Zhejiang Key Group Project in Scientific Innovation [2010R50042]
出版者	BIOMED CENTRAL LTD
出版地	LONDON
ISSN	1471-2407
卷号	15 期号:1 页码:276
DOI	10.1186/s12885-015-1307-9
页数	9
WOS类目	Oncology
WOS研究方向	Oncology
WOS记录号	WOS:000353454100001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	25880284
PMC记录号	PMC4410475
SCOPUSEID	2-s2.0-84928323469
通讯作者地址	[Ji, Jiansong]Wenzhou Medical University,Chemical Biology Research Center,College of Pharmaceutical Sciences,Wenzhou, Zhejiang,325035,China
Scopus学科分类	Oncology;Genetics;Cancer Research
TOP期刊	TOP期刊
引用统计	被引频次：13[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/19387
专题	药学院（分析测试中心）_生物有机与药物化学研究中心温州医科大学其他_附属第五医院（丽水市中心医院）
通讯作者	Ji, Jiansong
作者单位	1.Wenzhou Medical University,Chemical Biology Research Center,College of Pharmaceutical Sciences,Wenzhou, Zhejiang,325035,China; 2.Wenzhou Medical Universtiy,College of Information Science and Computer Engineering,Wenzhou, Zhejiang,325035,China; 3.The Sixth Affiliated Hospital of Wenzhou Medical University,Department of Pharmacy,Lishui, Zhejiang,323000,China; 4.The Fifth Affiliated Hospital of Wenzhou Medical University,Department of Interventional Radiology,Lishui, Zhejiang,323000,China
第一作者单位	药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者单位	药学院（分析测试中心）_生物有机与药物化学研究中心
第一作者的第一单位	药学院（分析测试中心）_生物有机与药物化学研究中心
推荐引用方式 GB/T 7714	Wu, Jianzhang,Wei, Tao,Tang, Qinqin,et al. Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer[J]. BMC CANCER,2015,15(1):276.
APA	Wu, Jianzhang., Wei, Tao., Tang, Qinqin., Weng, Bixia., Li, Wulan., ... & Ji, Jiansong. (2015). Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer. BMC CANCER, 15(1), 276.
MLA	Wu, Jianzhang,et al."Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer".BMC CANCER 15.1(2015):276.