Multi-Targeted Histone Deacetylase Inhibitors in Cancer Therapy

The heterogeneous nature of cancer requires a comprehensive approach for attacking the multiple mechanisms underlying the initiation and progression of cancers. Histone deacetylase inhibitors (HDACi) have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. Studies have revealed that HDACi are synergistic with diverse classes of anticancer therapies including targeted therapeutics and conventional anticancer agents. Extensive medicinal chemistry efforts have yielded a wide range of chemical structures, indicative of the structural flexibility of HDACi. These findings have supported a strategy to generate multi-targeted HDACi by combining structural features from HDACi and other anticancer agents. HDACi can also be connected to a motif that allows for a selective delivery. Highlighting current examples, this brief review focuses on the rational design of multi-targeted inhibitors based on the examination and manipulation of chemical structures.