Histone deacetylase inhibitors (HDACi) are a promising new group of targeted anti-cancer agents. Several are in clinical trials. Suberoylanilide hydroxamic acid (SAHA) has advanced to Phase II trials showing anti-tumor activity in patients with both solid tumors and hematologic malignancies at doses well tolerated by patients. In addition, HDACi are interesting in terms of their biologic activity and potential non-cancer applications in neurodegenerative diseases, auto-immune disorders, and others.

The paper focuses on the new discovery of HDACi and their effect on tumors. The aspect that is particularly interesting are the findings that, despite the widespread distribution of HDACs in chromatin, the effect of inhibition of these enzymes is selective in that only two to five percent of expressed genes are altered in their transcription in different transformed cells.

The discovery and development of small molecules, such as SAHA, as inhibitors of the enzymes, HDACs, has opened a newly targeted approach to the treatment of many different types of cancers. SAHA has been developed as an orally administered anti-cancer agent. In Phase I and II clinical trials, SAHA has been shown to be well-tolerated at doses that have significant anti-cancer activity.

In the mid-1970s, I became interested in understanding the effect of DMSO (dimethylsulfoxide), which Charlotte Friend, of Mt. Sinai Hospital in New York City, had shown caused virus-induced erythroleukemia cells to stop growing and differentiating. We investigated the structure of DMSO required for this effect and showed it was the polar group. Along with Ronald Breslow, Professor of Chemistry at Columbia University, we pursued extensive structure-activity studies, focusing as well on the biologic effects of these agents. Over the years, these studies led us to discover that hybrid polar hydroxamic acid based molecules (M.W.~300) were potent inhibitors of HDACs. With numerous collaborators we defined the effects of inhibiting HDACs on cell growth and gene expression, and discovered their anti-tumor activity, initially in vitro and in tumor-bearing animals and, beginning in mid-2000, in clinical trials with the lead compound, SAHA.