文献类型：期刊文献

英文题名：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

作者：Zhang, Jin[1,2];Zhou, Jing[1,2];Ren, Xiaomei[1,2];Diao, Yanyan[3];Li, Honglin[3];Jiang, Hualiang[3];Ding, Ke[1,2];Pei, Duanqing[1,2]

机构：[1]Chinese Acad Sci, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China;[2]Chinese Acad Sci, Inst Biol Chem, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

年份：2012

卷号：30

期号：2

起止页码：490

外文期刊名：INVESTIGATIONAL NEW DRUGS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000300160800007)】；

基金：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).

语种：英文

外文关键词：D181; Receptor tyrosine kinase; G1/M arrest; Tubulin polymerization

摘要：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 PDGFR beta. 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.