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 (IC50 = 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.