Progress in the Discovery of Macrocyclic Histone Deacetylase Inhibitors for the Treatment of Cancer

Background: Histone deacetylases (HDACs) play key roles in many biological phenomena and HDAC inhibition has been proved to be an effective strategy in cancer therapy. Over the last few decades, a plethora of structurally diverse HDAC inhibitors have been reported for a broad range of tumor indications. Among them, macrocyclic HDAC inhibitors, including cyclic peptides, depsipeptides and peptidomimetics, etc., have drawn lots of interests because of the fact that macrocyclic HDAC inhibitors have the potential for member or isoform selective inhibition. Conclusion: Macrocyclic HDAC inhibitors present an excellent opportunity for the selective modulation of HDAC inhibitors due to their complex recognition cap group moieties. However, compared with the structurally simpler synthetic HDAC inhibitors, efforts to develop macrocyclic HDAC inhibitors have been so far modestly successful with only one compound (romidepsin) approved for the cancer treatment. Development of macrocyclic HDAC inhibitors are hampered by the complex reaction schemes required for their synthesis. We expect that in the near future, more macrocyclic HDAC inhibitors will be identified from natural products; and further modification or SAR studies will be made on these or already known natural macrocyclic HDAC inhibitors. More selective drug-like macrocyclic HDAC inhibitors will be designed and identified after understanding the interactions between the ligand and the HDACs.