This was an overall excellent meeting with a fruitful mix of participants from industry and academia. It consisted of two half-day pre-conference workshops on Dec 4th and two days of seminar presentations and discussions Dec 5th and 6th, 2012. The general tenor of the meeting was set at the start by Chas Bountra, Chief Scientist at SGC, who made an appeal to all participants to collaborate closely, share results and resources and follow the open access model SGC has put forward, all with the goal of generating epigenetic drugs as research tools and as effective therapeutics, quickly. Working together to achieve this was the key message.
Translating Chromatin Biology into Clinically Effective Drugs
Patrick Trojer, Constellation
Patrick told us about Constellation’s efforts to chemically target EZH2 mutated in the SET domain, such as the Y641N mutation, which favors the enzyme’s trimethylation activity over dimethylation, representing a gain of function found in human tumors. The identified active compound discussed showed selectivity in vitro for EZH1 and 2 over other histone methyltransferases and affected cellular levels of dimethyl and trimethyl H3K27 while not affecting monomethyl levels. In addition, the inhibitor had specific anti-proliferative activity against cancer cell lines containing EZH2 mutations and was active in CPI-300 prostate cancer xenograft models. Of interest, transcriptional changes, altered global histone modification levels and induction of cell death did not occur in response to the compound in cells until 4-10 days of treatment, suggesting that the kinetics of functional events downstream of EZH2 inhibition (such as histone turnover) may dictate the phenotypic response time.
Novel High Throughput in vitro and in cyto Assays in Epigenetics Research
Mathieu Arcand, Perkin Elmer
Mathieu shared the wide number of biochemical and cell based assays developed and being made available to the scientific community by Perkin Elmer for epigenetic research and drug discovery. These tools can be mixed and matched for specific applications. Two particular technologies were highlighted: LANCE and alpha-screen assays. The LANCE assays are based on FRET methodology and are of particular interest when measuring interactions in the order of 9-10 nanometer distances. The alpha-screen assays rely on the production and diffusion of a singlet oxygen upon excitation of a donor bead. Because of the diffusion distance of the singlet oxygen, the acceptor bead can pick up the signal up to 200 nanometers away, allowing for quantification of longer range interactions. These assays have flexible components that allow the end user to mix and match elements to measure the desired interactions between combinations of peptides, compounds and/or proteins, all bridged by the tagged donor and acceptor beads at either end of the complex. Special plate readers with alpha screen technology capabilities are required.
Using Epigenetic Targets to approach autoimmune and inflammatory disease indications
Rab Prinjha, GlaxoSmithKline
The presentation started with the introduction of the idea that potentially, genes of similar function whose expression may need to be coordinately regulated may be marked by similar epigenetic marks, defining gene subgroups of biological relevance in the context of response to stimulation. This idea was illustrated by examples of epigenetic co-regulation of secondary response genes upon LPS induction of inflammation. Genes that were sensitive to modulation by the bromodomain inhibitor I-BET5762 were marked by distinct patterns of DNA methylation and histone acetylation/methylation at the onset and were exclusively secondary response genes and not early genes. Thus in this case the response to the inhibitor could be partly predicted in macrophages by the underlying epigenetic marks. Whether this will be a general principle that could apply to other functionally related group of genes will require further investigation in other systems.
Among other topics of interest discussed, were LSD1 inhibitors, the importance of co-developing biomarkers alongside epigenetic drugs, several non-cancer applications of epigenetic compounds (including inflammation and rheumatoid arthritis), and considerations regarding the safety and toxicology of epigenetic compounds from an organismal point of view and taking into account possible drug induced changes that could potentially be heritable. Much food for thought indeed!
EpiGenie would like to thanks Elisabeth D. Martinez, Ph.D, Assistant Professor at UT Southwestern Medical Center at Dallas for contributing this coverage.