Paul A. Marks: Histone Deacetylases and Histone Deacetylase Inhibitors: Development and Discovery of New Targeted Anticancer Drugs

Over the past several years, our laboratory has focused on the role of histone deacetylases (HDACs) and the development of inhibitors of these enzymes which are effective in arresting cell growth and selectively inducing cancer cell death. There are 18 HDACs in humans of which 11 are zinc dependent. In addition to histones, the zinc dependent HDACs have many nonhistone protein substrates involved in regulation of gene expression, cell proliferation, migration, and death, and in angiogenesis. Our laboratory discovered and developed an hydroxamic acid inhibitor of zinc dependent HDACs, suberoylanilide hydroxamic acid (SAHA)(vorinostat). This HDAC inhibition is effective in inducing cell growth arrest and cell death of many transformed cells in culture and inhibition of tumor growth in animal model with little or no toxicity. In clinical trials, SAHA has efficacy in hematologic and solid tumors at doses that are well tolerated. Vorinostat has been approved by the FDA for use in treatment of cutaneous T-cell lymphoma — the first of the HDACi to be approved for cancer treatment. Our laboratory’s focus is to understand the biological activity of the different zinc dependent HDACs. We discovered that HDAC6, an unique zinc dependent HDAC that has two catalytic sites; a ubiquitin binding site and is primarily cytoplasmic, has specific substrates involved in regulation of apoptotic cell death and cell migration. HDAC6 does not deacetylate histones. Currently, we are developing HDAC6 selective inhibitors and investigating the biological role of this HDAC and its potential as a target for treatment of cancers, as well as, other diseases.