Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.

The family of histone deacetylases (HDAC) has been associated with various processes in the development and growth of many cancers. Selective inhibition improves the tolerability of HDAC inhibitors, while dual targeting of synergistic targets improves the efficacy of cancer therapy. In this article, we report the design, molecular docking studies and ADMET predictions of nine novel HDAC6/WEE1, HDAC6/GLS1 and SIRT2/AURKA dual inhibitors. The developed compounds show comparable or better docking results and ADMET properties than reference co-crystal ligands.