Significance Cancer cells derived from mesenchymal tissues or induced to adopt a mesenchymal state have been demonstrated to be largely resistant to standard chemotherapies, necessitating the identification of new effective treatment strategies. From a high throughput screen, we have discovered FiVe1, a compound capable of irreversibly inhibiting the growth of mesenchymally transformed cancer cells by binding to and interfering with the organization and phosphorylation of vimentin (VIM) during mitosis. In contrast to the many naturally and synthetically derived compounds targeting microtubules, we report that chemically targeting an intermediate filament protein, VIM, promotes mitotic catastrophe. As VIM expression is restricted to mesenchymal cells, these results provide a mechanistic basis toward developing genotype-selective chemotherapeutics for the treatment of mesenchymal cancers.