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

Abstract

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.

Diaryl Urea: A Privileged Structure in Anticancer Agents

“…Moreover it inhibits DNA, RNA and protein synthesis in CEM (human lymphoma) cells with similar IC 50 values [49]. Other analogs of sorafenib have been obtained by replacement of the 4-phenoxypyridine moiety with the phenyl-(2-cyano-4-hydroxyphenyl) moiety [50]. The compound 2, D181 functions as both a multi-kinase inhibitor and a tubulin polymerization enhancer.…”

Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

“…The compound demonstrated antiproliferative effects in several cancer cell lines and inhibited tumor growth in LoVo and HT29 mice xenografts. Compound 125 showed significant antiangiogenic effect, and this may be due to combination of microtubule disruption and VEGFR inhibition …”

“…Compound 125 showed significant antiangiogenic effect, and this may be due to combination of microtubule disruption and VEGFR inhibition. 231 Boger and co-workers reported several formerly inaccessible C20′ urea derivatives of vinblastine with the aim of improving their affinity for tubulin and cellular activity. A very interesting finding was the steric tolerance for the size of a C20′ substituent.…”

A Simple and Efficient Synthesis of Diaryl Ureas with Reduction of the Intermediate Isocyanate by Triethylamine

“…The urea group plays an important role in agricultural, supramolecular, and medicinal chemistry. [1][2][3][4][5][6] For example, recent reports have cited examples of ureas as antimalarial agents, 7,8 cardiac-specific myosin activators, 9 anaplastic lymphoma kinase inhibitors, 10 tyrosine and Raf kinase inhibitors, 11 soluble epoxide hydrolase inhibitors for the treatment of diabetes, hypertension, stroke, and inflammatory diseases. 12,13 Moreover, urea derivatives also impart important function in organic synthesis as intermediates and bifunctional organocatalysts.…”