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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

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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.

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Acknowledgment

This work was financially supported by the 100-talent program of CAS, CAS grant (KSCX2-YWR-27), the National Natural Science Foundation (Grant # 90813033) and the National High Technology Research and Development Program (Grant # 2008AA02Z420, 2009CB940904, 2010CB529706).

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Authors and Affiliations

  1. Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Road, Guangzhou Science Park, Guangzhou, Guangdong Province, 510530, China

    Jin Zhang, Jing Zhou, Xiaomei Ren, Ke Ding & Duanqing Pei

  2. School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China

    Yanyan Diao, Honglin Li & Hualiang Jiang

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  1. Jin Zhang
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  2. Jing Zhou
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  3. Xiaomei Ren
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  4. Yanyan Diao
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  5. Honglin Li
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  6. Hualiang Jiang
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  7. Ke Ding
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  8. Duanqing Pei
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Correspondence to Ke Ding or Duanqing Pei.

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Zhang, J., Zhou, J., Ren, X. et al. 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. Invest New Drugs 30, 490–507 (2012). https://doi.org/10.1007/s10637-010-9577-1

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