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Preface [Hot topic: Histone Deacetylase Inhibitors (Guest Editor: Kristof Van Emelen)]

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Histone Deacetylases (HDACs) represent a family of enzymes that compete with histone acetyltranferases (HATs) to modulate chromatin structure and regulate transcriptional activity via changes in the acetylation status of nucleosomal histones. The opposing functions of HATs and HDACs in both activating and repressing transcription by controlling the tightness of nucleosomal integrity, reflect the regulatory processes that are involved in turning genes on or off.

Several forms of cancer are characterized by an altered expression or mutation of genes that encode HATs or HDACs. Similarly, aberrant repression of genes mediated by HDACs, is associated with the pathogenesis of various types of cancer, including acute leukemia and non-Hodgkin's lymphoma. The resulting alterations in chromatin structure can impringe on normal cellular differentiation and result in tumor onset and progression.

Furthermore, HDAC inhibitors from various structural families induce histone hyperacetylation, reactivate suppressed genes and consequently, inhibit the cell cycle, activate differentiation programmes or induce apoptosis.

During the past decade, the potent inhibition of tumor progression in rodent models has generated much interest and excitement, but lately the field has come of age, with preliminary successes of HDAC inhibitors in preclinical trials, and even several compounds in Phase I and II clinical trials.

In conclusion, HDAC inhibitors are exciting new anti-cancer agents and despite the fact that there is still much to learn about the exact molecular events that underlie their effects, the remarkable tumor specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibition as a promising strategy for targeted cancer therapy.

This Hot Topic issue addresses various approaches towards the identification of potent, potentially subtype specific HDAC inhibitors. Whereas the first generation of HDAC inhibitors has provided much insight in the specific functions of HDACs, the herein reported drug discovery programs focus on second generation HDAC inhibitors, some of which have reached clinical evaluation. Various strategies have been employed by the different research groups, such as co-crystallization, Structure Based Drug Design, peptide chemistry, synthesis of small molecule inhibitors through combinatorial and directed medicinal chemistry.

It is hoped that with this selection of topics, the reader is provided with a perspective on some of the most advanced developments of HDAC inhibitors and a better understanding of the potential of HDAC inhibition in the treatment of cancer.
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Document Type: Book Review

Affiliations: Department of Medicinal Chemistry Johnson & Johnson Pharmaceutical Research and Development Turnhoutseweg 30 2340 Beerse Belgium

Publication date: 2003-11-01

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