Histone deacetylase inhibitors
SummaryThe field of histone deacetylase inhibitors is moving into a new phase of development. The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has now started to produce success in the clinic, particularly in the field of oncology. Over the next few years experts believe that as first generation HDAC inhibitors produce clinical benefits and second generation inhibitors are rationally designed with improved specificity
The field of histone deacetylase inhibitors is moving into a new phase of development. The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has now started to produce success in the clinic, particularly in the field of oncology. Over the next few years experts believe that as first generation HDAC inhibitors produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class will emerge as a new class of cancer treatment.
This report published in 2005 by the drug development analysts introduces the concept of histone plasticity and the molecular control of transcription by histone deacetylases. The report continues with an overview of the histone deacetylases and a discussion of the therapeutic effects of their inhibitors. The report provides an in depth profile of HDAC inhibitors in development and concludes with a detailed analysis of the benefits to be gained through HDAC inhibition and the hurdles that must be negotiated by drug development organizations while advancing this field. ’s primary conclusion is that HDAC inhibitors offer the potential to synergize with both classic and targeted cancer therapies. The most advanced therapeutic candidates such as SAHA and FK228 are already showing promising activity. This potential should be further realized as rationally designed inhibitors developed by companies such as MethyGene and TopoTarget emerge whose pharmacological profile targets those histone deacetylases key to cancer progression.
The authors of Histone deacetylase inhibitors: Moving from the bench to a promising candidate for classic and targeted cancer therapies set out to take the mystery out of molecular biology while at the e time analyzing the potential and the pitfalls in this exciting field. The report is targeted at all involved in drug development extending from preclinical drug discovery personnel to business development managers and strategists.
Summary of key issues & conclusions
- 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