Aminosuberoyl hydroxamic acids (ASHAs): A potent new class of HDAC inhibitors

Exploring branched substrate-like HDAC inhibitors, mimicking the peptide substrate, lead to a series of aminosuberoyl hydroxamic acids (ASHAs) with remarkable HDAC inhibitory activity. Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are currently in advanced clinical trials for the treatment of cancer. Vorinostat (Zolinza™, SAHA) is a hydroxamic acid approved for the treatment of patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. As part of an on-going effort to better understand the nature of the HDAC enzyme/inhibitor interaction and design highly effective HDAC inhibitors, we herein report the design, synthesis and HDAC inhibitory activity of a vorinostat-derived series of substrate-based HDAC inhibitors.