Design, synthesis and antitumor activity study of tubulin/HDAC6 dual targeting inhibitor

Cancer combination therapy is a novel strategy to circumvent drug resistance in highly metastatic and advanced malignancies. To this end, we designed and synthesized a series of dual-targeting compounds that target tubulin and HDAC6 simultaneously. Out of them, compound named as 6-4 possessed potent inhibitory activity against tubulin polymerization and strong antiproliferative activity to the cancer cell lines tested. 6-4 was able to inhibit tubulin polymerization and disrupt the microtubule network of tumor cells. Significant downregulation of tubulin deacetylation was also observed after the treatment of 6-4 which indicated its inhibition toward HDAC6. Mechanism studies demonstrated that 6-4 could arrest cell cycle in G2/M phase and induce apoptosis in a dose-dependent manner. In addition, 6-4 can suppress metastasis of Hela cells, and significantly inhibit the formation of HUVEC tubes. All these results suggest that 6-4 should be a promising candidate for the treatment of cancer.