Abstract
On behalf of the Journal of Biomolecular Screening (JBS), it is with great pleasure that we present the first of two special issues focused on epigenetics and drug discovery.
In its broadest sense, epigenetics describes the complex molecular processes that control the regulation and inheritance of gene expression patterns in healthy development and disease. It holds the potential to revolutionize basic science, medicine, and drug discovery, much like the discovery of the genetic code almost 60 years ago. The significance of epigenetics is magnified when one considers that it defines mechanisms for dynamic, semi-reversible biochemical responses to environmental conditions ranging from diet to psychological stress or, in other words, a developmental plasticity in which early life experiences influence disease susceptibility in later life and even in subsequent generations. Epigenetic mechanisms provide the basis for the extraordinary complexity and specialization that occur within differentiated cells, which goes well beyond the answers provided by the (relatively simple) genetic code. As such, the area is poised for major discoveries, many of which are likely to be underpinned by the assay and screening approaches described in two special issues of JBS.
The approval of epigenetic drugs for hematological cancers (DNA methylation [DNMT] inhibitors azacitidine and decitabine for myelodysplastic syndrome, as well as histone deacetylase [HDAC] inhibitors vorinostat and romidepsin for cutaneous T cell lymphoma) has demonstrated that modulation of relatively broad epigenetic regulatory processes can show beneficial efficacy and safety profiles in defined patient groups. The impact of these early drugs is likely to widen as combination trials with targeted anticancer agents progress. This precedent has attracted the interest of a large and growing number of pharmaceutical and biotech companies (currently estimated at around 40 companies worldwide) working on refinements in DNA methyltransferase and HDAC inhibition, as well as exploring the effects of modulating additional histone-modifying proteins, including lysine or arginine methyltransferases, lysine demethylases, and domains that recruit transcriptional regulators to histone modifications, particularly acetyl-lysine and methyl-lysine. These efforts are mirrored by wide-ranging public sector initiatives aimed at unraveling the complex interplay of combinatorial DNA and histone modifications in transcriptional regulation and collecting epidemiological epigenomic fingerprint data leading to biomarker development for diagnostic, prognostic, and theranostic patient assessment, as well as clinical association for potential new molecular targets.
Together, the growing epigenetics research community has demonstrated epigenetic differences between healthy cells and those from patients with a variety of diseases beyond cancer, including immunoinflammatory, metabolic, neurological, and psychiatric diseases. In many cases, genetic knockdown, mutation, and/or overexpression have been used to demonstrate the roles of individual epigenetic modulatory proteins in these differences, together with the therapeutic potential of reversing the epigenetic aberrations. As in other areas of biomedical research, it remains to be seen whether such promising outcomes can be recapitulated with small-molecule modulators and translated to clinical benefit. To this end, early efforts to generate small molecules that can be used as probes in chemical biology experiments are essential to speed the process of identifying the key players in the epigenetic cast.
Given the central role of epigenetic mechanisms, these classes of targets seem certain to provide opportunities for understanding and treating diseases well beyond the current focus in cancer. The potential of epigenetic-modulator compounds to alter gene expression in an unexpected and perhaps durable manner (i.e., long after drug elimination, perhaps even inheritable in some cases) may also result in some unique challenges with respect to drug safety.
In JBS’s two special issues on epigenetic-targeted drug discovery, we have assembled contributions from leading public sector, biotechnology, and pharmaceutical groups that are applying 21st-century drug discovery techniques to allow the generation and characterization of small-molecule inhibitors of epigenetic regulatory proteins. It is a reflection of the current importance of this research area that we required two issues of the journal to capture all of the excellent papers that were submitted. In this first issue, we start with reviews covering the whole area of assays for epigenetic targets generally and (from Bob Campbell, the editor-in-chief of JBS) the fascinating and sometimes controversial area of sirtuins. 1 The subsequent articles in this issue focus mainly on systems that interact with histone acetyl marks. We are fortunate to have articles that cover the writers (histone acetyltransferases),2,3 readers (bromodomains), 4 and erasers (HDACs)5,6 of histone acetyl marks. This coverage is combined with some exciting new ways to assay these targets and reports of successful hit discovery efforts.
In the January 2012 issue of JBS, the second part of our epigenetics series, the articles focus on systems that interact with methyl marks, including methyl writers (histone methyltransferases) and erasers (histone demethylases). This issue will also include articles describing methods to measure histone marks in cells.
We hope you find the subsequent articles interesting and engaging. The whole area of epigenetics seems poised to make great progress and is at a stage where biomolecular screening, whether to identify new probes to understand biology or potential new medicines, is critical.
