Discovery of a Series
of Thiazole Derivatives as Novel
Inhibitors of Metastatic Cancer Cell Migration and Invasion
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Abstract
Effective inhibitors of cancer cell migration and invasion
can
potentially lead to clinical applications as a therapy to block tumor
metastasis, the primary cause of death in cancer patients. To this
end, we have designed and synthesized a series of thiazole derivatives
that showed potent efficacy against cell migration and invasion in
metastatic cancer cells. The most effective compound, <b>5k</b>, was found to have an IC<sub>50</sub> value of 176 nM in the dose-dependent
transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, <b>5k</b> also blocked about 80% of migration in HeLa and A549 cells
and 60% of invasion of MDA-MB-231 cells. Importantly, the majority
of the derivatives exhibited no apparent cytotoxicity in the clonogenic
assays. The low to negligible inhibition of cell proliferation is
a desirable property of these antimigration derivatives because they
hold promise of low toxicity to healthy cells as potential therapeutic
agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy
demonstrate that compound <b>5k</b> substantially reduced cellular
f-actin and prevented localization of fascin to actin-rich membrane
protrusions. These results suggest that the antimigration activity
may result from impaired actin structures in protrusions that are
necessary to drive migration