Investigational New Drugs

, Volume 30, Issue 2, pp 490–507

A new diaryl urea compound, D181, induces cell cycle arrest in the G1 and M phases by targeting receptor tyrosine kinases and the microtubule skeleton

Authors

  • Jin Zhang
    • Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and HealthChinese Academy of Sciences
  • Jing Zhou
    • Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and HealthChinese Academy of Sciences
  • Xiaomei Ren
    • Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and HealthChinese Academy of Sciences
  • Yanyan Diao
    • School of PharmacyEast China University of Science and Technology
  • Honglin Li
    • School of PharmacyEast China University of Science and Technology
  • Hualiang Jiang
    • School of PharmacyEast China University of Science and Technology
    • Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and HealthChinese Academy of Sciences
    • Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and HealthChinese Academy of Sciences
PRECLINICAL TRIALS

DOI: 10.1007/s10637-010-9577-1

Cite this article as:
Zhang, J., Zhou, J., Ren, X. et al. Invest New Drugs (2012) 30: 490. doi:10.1007/s10637-010-9577-1

Summary

Receptor tyrosine kinases (RTKs) modulate a variety of cellular events, including cell proliferation, differentiation, mobility and apoptosis. In addition, RTKs have been validated as targets for cancer therapies. Microtubules are another class of proven targets for many clinical anticancer drugs. Here, we report that 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-cyano-4-hydroxyphenyl)urea (D181) functions as both a receptor tyrosine kinase inhibitor and a tubulin polymerization enhancer. D181 displayed potent inhibitory activities against a panel of RTKs, including Flt3, VEGFR, cKit, FGFR1 and PDGFRβ. D181 also enhanced tubulin polymerization and modified the secondary structure of tubulin proteins to disrupt their dynamic instability. Because of synergistic cooperation, D181 strongly inhibited the proliferation of various cancer cell lines, induced LoVo cell cycle arrest in the G1 and M phases and suppressed tumor growth in nude mice bearing human LoVo and HT29 xenografts. Our studies have provided a new, promising lead compound and novel clues for multi-target anticancer drug design and development.

Keywords

D181Receptor tyrosine kinaseG1/M arrestTubulin polymerization

Copyright information

© Springer Science+Business Media, LLC 2010