- Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2
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Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.
- Wei, Dengshuai,Fan, Haoru,Zheng, Kun,Qin, Xuemei,Yang, Leifu,Yang, Yajuan,Duan, Ye,Zhang, Qiang,Zeng, Chengchu,Hu, Liming
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- Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis
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Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study.
- Huang, Zhi,Zhao,Qin, Zhongxiang,Li, Yongtao,Wang, Tianqi,Zhou, Wei,Zheng, Jianyu,Yang, Shengyong,Shi, Yi,Fan, Yan,Xiang, Rong
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- Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate
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A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhi
- Li, Yongtao,Guo, Qingxiang,Zhang, Chao,Huang, Zhi,Wang, Tianqi,Wang, Xin,Wang, Xiang,Xu, Guangwei,Liu, Yanhua,Yang, Shengyong,Fan, Yan,Xiang, Rong
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supporting information
p. 3231 - 3237
(2017/07/07)
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- Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors
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In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to p
- Zhao, Yanmei,Zhang, Jiankang,Zhuang, Rangxiao,He, Ruoyu,Xi, Jianjun,Pan, Xuwang,Shao, Yidan,Pan, Jinming,Sun, Jingjing,Cai, Zhaobin,Liu, Shourong,Huang, Weiwei,Lv, Xiaoqing
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p. 3195 - 3205
(2017/05/25)
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- Discovery of anilinopyrimidines as dual inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and cellular activity
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Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed
- Zhan, Zhengsheng,Ai, Jing,Liu, Qiufeng,Ji, Yinchun,Chen, Tiantian,Xu, Yechun,Geng, Meiyu,Duan, Wenhu
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supporting information
p. 673 - 678
(2014/07/07)
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