Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects.

Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor TH-0 as the lead compound. Among them, compound TH-6 exhibited the most potent antiproliferative activity (IC 50 = 18-30 nM) against a panel of cancer cell lines. As expected, TH-6 inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further in vivo antitumor assay displayed that TH-6 effectively inhibited tumor growth with no apparent toxicity. More importantly, TH-6 disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, TH-6 deserves to be further investigated for the new approach to clinical cancer therapy.