Discovery of Potent and Isoform‐selective Histone Deacetylase Inhibitors Using Structure‐based Virtual Screening and Biological Evaluation

Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC‐27, AGS, MDA‐MB‐231, A549, MCF‐7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC‐27 cells‐derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC‐targeting inhibitor for solid tumor therapy.