Sounds like ideal anti-cancer agents. The pharmaceutical industry ought to have ongoing trials right now so they can be approved. Here's some abstracts that show why these things probably should be approved as soon as possible. Roger ------ Expert Opin Investig Drugs. 2002 Dec;11(12):1695-713. Histone deacetylase inhibitors: from target to clinical trials. Kelly WK, O'Connor OA, Marks PA. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post- translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses. -------- Curr Opin Oncol. 2001 Nov;13(6):477-83. Related Articles, Links Histone deacetylase inhibitors as new cancer drugs. Marks PA, Richon VM, Breslow R, Rifkind RA. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. [email protected] Histone deacetylase inhibitors are potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. Histone deacetylases and the family of histone acetyl transferases are involved in determining the acetylation of histones, which play a role in regulation of gene expression. Radiograph crystallographic studies reveal that the histone deacetylase inhibitors, suberoylanilide hydroxamic acid and trichostatin A, fit into the catalytic site of histone deacetylase, which has a tubular structure with a zinc atom at its base. The hydroxamic acid moiety of the inhibitor binds to the zinc. Histone deacetylase inhibitors cause acetylated histones to accumulate in both tumor and peripheral circulating mononuclear cells. Accumulation of acetylated histones has been used as a marker of the biologic activity of the agents. Hydroxamic acid-based histone deacetylase inhibitors limit tumor cell growth in animals with little or no toxicity. These compounds act selectively on genes, altering the transcription of only approximately 2% of expressed genes in cultured tumor cells. A number of proteins other than histones are substrates for histone deacetylases. The role that these other targets play in histone deacetylase inducement of cell growth arrest, differentiation, or apoptotic cell death is not known. This review summarizes the characteristics of a variety of inhibitors of histone deacetylases and their effects on transformed cells in culture and tumor growth in animal models. Several structurally different histone deacetylase inhibitors are in phase I or II clinical trials in patients with cancers. ------ Curr Opin Investig Drugs. 2003 Dec;4(12):1422-7. Related Articles, Links HDAC inhibitors for the treatment of cancer. Secrist JP, Zhou X, Richon VM. Aton Pharma Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, USA. [email protected] Histone deacetylase (HDAC) inhibitors are a new class of cancer chemotherapeutics in clinical development that target the family of enzymes that catalyze the removal of the acetyl modification on lysine residues of proteins, including the core nucleosomal histones H2A, H2B, H3 and H4. The balance of nucleosomal histone acetylation is maintained through the opposing actions of histone acetyltransferases (HATs) and HDACs, and plays an important regulatory role in gene transcription. Alterations in both HATs and HDACs have been identified in tumor cells and may contribute to the altered gene expression found in many cancers. Inhibitors of HDAC activity induce cell cycle arrest, differentiation or apoptosis in tumor cells, and inhibit tumor growth in a variety of rodent models of cancer. Several structurally diverse HDAC inhibitors have entered clinical trials and are demonstrating encouraging antitumor activity in a variety of cancer types. As we learn more about these enzymes and the biological processes that they regulate, a strong rationale is emerging for the development of HDAC inhibitors as anticancer agents. ------- Anticancer Drugs. 2002 Jan;13(1):1-13. Related Articles, Links Histone deacetylase inhibitors in cancer treatment. Vigushin DM, Coombes RC. Department of Cancer Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital Campus, London W12 0NN, UK. [email protected] Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo. The effects of HDAC inhibitors on gene expression are highly selective, leading to transcriptional activation of certain genes such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1 but repression of others. HDAC inhibition not only results in acetylation of histones but also transcription factors such as p53, GATA-1 and estrogen receptor-alpha. The functional significance of acetylation of non-histone proteins and the precise mechanisms whereby HDAC inhibitors induce tumor cell growth arrest, differentiation and/or apoptosis are currently the focus of intensive research. Several HDAC inhibitors have shown impressive antitumor activity in vivo with remarkably little toxicity in preclinical studies and are currently in phase I clinical trial. The focus of this review is the development and clinical application of HDAC inhibitors for the treatment of cancer. ------- Curr Med Chem. 2003 Nov;10(22):2351-8. Related Articles, Links From discovery to the coming generation of histone deacetylase inhibitors. Yoshida M, Matsuyama A, Komatsu Y, Nishino N. Chemical Genetics Laboratory, RIKEN and CREST, JST, Saitama, Japan. [email protected] Trichostatin A (TSA) is a Streptomyces metabolite that causes differentiation of murine erythroleukemia cells as well as specific inhibition of the cell cycle of some lower eukaryotes and mammalian cells. The targeted molecule of TSA has been shown by genetic and biochemical analyses to be histone deacetylases (HDACs). Histone acetylation is a key modification to control transcription, and HDACs are profoundly involved in pathogenesis of cancer through removing acetyl groups from histones and other transcriptional regulators. Trapoxin (TPX) and FK228 (also known as FR901228 and depsipeptide because FK228 = FR901228 = depsipeptide), structurally unrelated microbial metabolites, were also shown to inhibit HDACs. These HDAC inhibitors cause cell cycle arrest, differentiation and/or apoptosis of many tumors, suggesting their usefulness for chemotherapy and differentiation therapy. In addition, HDAC inhibitors play important roles in identifying the specific function of the enzymes. Indeed, we identified tubulin as one of the substrates of HDAC6 by means of differential sensitivity to HDAC inhibitors. Since recent studies have revealed that HDACs are structurally and functionally diverse, it should be important to develop inhibitors specific to individual enzymes as more promising agents for cancer therapy. We have synthesized novel TSA/TPX hybrids, which will serve as a basis for developing enzyme-specific HDAC inhibitors.