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AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR

  1. Yuanfeng Zhou1,
  2. Yi Chen1,
  3. Linjiang Tong1,
  4. Hua Xie1,
  5. Weiwei Wen1,
  6. Jie Zhang1,
  7. Yong Xi1,
  8. Yanyan Shen1,
  9. Meiyu Geng1,
  10. Yuanyuan Wang2,
  11. Hualiang Jiang2,
  12. Cheng Luo2,
  13. Liping Lin1,*,
  14. Jian Ding1,*

Article first published online: 26 SEP 2012

DOI: 10.1111/j.1582-4934.2012.01541.x

Issue

Journal of Cellular and Molecular Medicine

Journal of Cellular and Molecular Medicine

Volume 16, Issue 10, pages 2321–2330, October 2012

Total views since publication: 253

Additional Information

How to Cite

Zhou, Y., Chen, Y., Tong, L., Xie, H., Wen, W., Zhang, J., Xi, Y., Shen, Y., Geng, M., Wang, Y., Jiang, H., Luo, C., Lin, L. and Ding, J. (2012), AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR. Journal of Cellular and Molecular Medicine, 16: 2321–2330. doi: 10.1111/j.1582-4934.2012.01541.x

Author Information

  1. 1

    Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China

  2. 2

    Drug Discover and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China

* Correspondence to: Jian DING, Ph.D., Liping LIN, Ph.D.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences. 555 Zuchongzhi Rd, Shanghai, China
Tel.: 86 21 50806722
Fax: 86 21 50806722
E-mail: suozhang@mail.shcnc.ac.cn, lplin@mail.shcnc.ac.cn

Publication History

  1. Issue published online: 26 SEP 2012
  2. Article first published online: 26 SEP 2012
  3. Accepted manuscript online: 3 FEB 2012 12:35PM EST
  4. Manuscript Accepted: 12 JAN 2012
  5. Manuscript Received: 25 APR 2011

Funded by

  • Key New Drug Creation and Manufacturing Program. Grant Numbers: 2009ZX09301-001, 2009ZX09102-021
  • National Natural Science Foundation of China. Grant Numbers: 81072666, 20972174
  • Science and Technology Commission of Shanghai Municipality Pujiang Talent Program. Grant Number: 10PJ1412000

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Keywords:

  • multi-tyrosine kinases inhibitor;
  • angiogenesis;
  • anti-tumour activity

Abstract

Angiogenesis plays an important role in neoplastic transformation and progression as well as in the metastasis process of most human cancers. Herein, we identified AL3810 as a novel and orally bioavailable small molecular inhibitor with potent inhibitory activity against multiple tyrosine kinases involved in the process of angiogenesis. We found that AL3810 substantially inhibited the autophosphorylation of VEGFR2, PDGFRβ and FGFR1 in endothelial cells. Moreover, AL3810 exhibited potent anti-angiogenesis activity, manifested by significant inhibition of microvessel outgrowth of rat arterial ring and chickallantochorion membrane (CAM) in ex vivo angiogenesis models. Daily dosing of AL3810 has shown broad-spectrum anti-tumour activity in human kidney, pancreas, liver cancer xenograft models. Importantly, immunohistochemistry results demonstrated that the anti-tumour activity of AL3810 was closely correlated with its anti-angiogenesis activity, as demonstrated by a decreased microvessel area and reduced microvessel numbers in tumour tissues. The overall pharmacological profiles of AL3810 are superior to sorafenib. The clinical trials of AL3810 will soon be launched in China.

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