Histone deacetylase inhibitors: Moving from the bench to a promising companion for classic and targeted cancer therapies
- The field of HDAC inhibitors has been driven by their ability to modulate transcriptional activity. As a result, this therapeutic class is able to block angiogenesis and cell cycling, and promote apoptosis and differentiation. By targeting these key components of tumor proliferation, HDAC inhibitors have the potential to occupy an indomitable position in the fast-moving anticancer market. Although HDAC inhibitors display targeted anticancer activity per se a major reason why this class could play such a key role in oncology is that HDAC inhibition is able to improve the efficacy of existing agents as well as other new targeted therapies
- The evolution of HDAC research represents a fascinating area of cellular biology, spanning early work demonstrating the role of histone proteins in transcription. As a result of this early work it has become clear that HDACs modulate chromatin plasticity, facilitating protein:DNA interactions and thus transcriptional control. The number of HDAC enzyme subtypes has expanded considerably over the past few years, offering opportunities for the development of HDAC inhibitors with improved specificity. This report overviews the concept of histone remodeling, early HDAC research and the 11 known human class I and class II HDACs, as well as the related sirtuin family. This report also describes the signal transduction pathways, such as phosphorylation, dephosphorylation and SUMOylation, that are able to modulate HDAC activity, a further point of possible therapeutic intervention.
- Despite the youth of the field of HDAC inhibitors, an impressive body of data describes the ability of these molecules to modulate a wide variety of cellular functions, including cell differentiation, cell cycle progression, apoptosis, cytoskeletal modifications, and angiogenesis. A major aim of the present report was to overview this body of evidence and to demonstrate how this activity translates to therapeutic activity in models of cancer. The ability of HDAC inhibitors to synergize with classic chemotherapeutic agents as well as newer signal transduction pathway modulators and angiogenesis inhibitors represents an increasingly appreciated concept meaning that in contrast to the current wave of targeted therapies, the utility of HDAC inhibitors could span multiple cancers and be used alongside a broad range of therapeutics. This is a similar concept to that advanced for lead apoptosis modulators however the additional affects of HDAC inhibitors on cell cycle progression and angiogenesis should make successful HDAC inhibitors the partners of choice in combinatorial approaches to cancer.
- Over the past few years a handful of HDAC inhibitors have entered the clinic and the overall opinion is that these candidates are relatively safe. Amongst the HDAC inhibitors, Gloucester Pharmaceuticals’ histone deacetylase inhibitor FK228 is strategically placed to attain first-in-class status for the niche indications of peripheral T-cell lymphoma and cutaneous T-cell lymphoma. While the oral bioavailability of Merck’s SAHA will challenge FK228’s position in these settings, the appeal of FK228 is enhanced by a broader range of indications including chronic lymphocytic leukaemia and androgen independent prostate cancer.
- The next set of milestones for the field of HDAC inhibitors will center firmly on phase II data expected from studies evaluating FK228 in a wide range of cancers and alongside various existing treatments.
- We believe that once phase II studies have established the efficacy of FK228, the perceived appeal of the HDAC inhibitors will be considerably boosted and following this the next wave of development involving the advancement of second generation inhibitors targeting specific HDAC isoenzymes will take the field forwards still further. Adverse effects of first generation inhibitors are primarily hematological (neutropenia and thrombocytopenia) and cardiologic. Cardiac adverse effects are primarily asymptomatic electrophysiological changes. Next generation HDAC inhibitors include those which target specific HDAC isoenzymes contrasting with pan HDAC inhibitors such as SAHA and FK228. It is hoped that candidates such as those from MethylGene’s portfolio of rationally developed isoform-selective inhibitors will demonstrate improved efficacy and safety
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Table of Contents
1. Summary 2. Background 3. Eukaryotic Chromosome Packaging 4. HDAC: An Early History 5. Chromatin remodeling in transcriptional control 6. The Mammalian HDAC enzymes
7. The HDACs and transcriptional silencing – molecular strategies for achieving transcriptional control
8. HDAC:protein interactions
9. Post-translational modifications in the control of HDAC activity
10. Biological consequences of HDAC inhibition
11: Progress in chemical development of HDAC inhibitors
12. Profiles of HDAC inhibitors in clinical development
· Selected Preclinical 13. Strategic & Competitive Analysis
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