Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer

In this work, a series of novel dual inhibitors against both tubulin and histone deacetylase (HDAC) were designed and synthesized by integrating the natural product Millepachine with the key pharmacophore of HDAC inhibitors. Among them, compound 6 exhibited potent antiproliferative activity against 12 cancer cell lines, with IC50 values ranging from 0.020 to 0.244 μM. Mechanistic investigations revealed that compound 6 inhibited both tubulin polymerization (IC50 2.0 μM) and HDAC8 (IC50 0.110 μM), with 54-, 27- and 132-fold selectivity over HDAC1, HDAC4 and HDAC6, respectively. In an ovarian cancer xenograft mouse model, compound 6 exhibited significant inhibitory effect on tumor growth with a favorable safety profile. These findings identify compound 6 as a promising tubulin/HDAC8 dual inhibitor for further investigation.