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Targeting Histone Methyltransferases and Demethylases

 

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Histone methyltransferases (HMTs) and demethylases (HDMs) have rapidly emerged within the suite of epigenetic modifiers as new and promising classes of therapeutic targets. Recent genetic discoveries of HMT and HDM anomalies in various cancer types provide unique validation for selective and tumor-specific targeting of these enzymes. Clinical intervention is becoming increasingly feasible, but deciphering their role in complex disease, developing robust screening and hit-finding approaches for inhibitors, and addressing efficacy and safety remain challenging. Join pharmaceutical, biotech and academic researchers for practical solutions to challenges, while exploring the expanding arena of HMT and HDM therapeutics.

TUESDAY, OCTOBER 2


Discovery to Design: Assays, HTS & High-Quality Probes

1:30 pm Chairperson’s Remarks

Abdellah Allali-Hassani, Ph.D., Team Leader, Enzymatic Assays, Structural Genomics Consortium, University of Toronto

1:40 Screening Methods for Identification of Selective Inhibitors of Histone Methyltransferases

Abdellah Allali-Hassani, Ph.D., Team Leader, Enzymatic Assays, Structural Genomics Consortium, University of Toronto

Epigenetic regulations of gene expression, including mechanisms dependent on histone methylation, have been implicated in a variety of diseases including cancer. Increasing interest in identifying inhibitors of histone methyltransferases (HMTs) as targets for a new generation of therapeutics, necessitates developing optimized screening methods for these enzymes. Here, we report assay development and screening methods for more than 16 HMTs and their application in discovery of selective inhibitors.

2:10 Development of a Novel Demethylase Assay and High-Throughput Screening for Demethylase Inhibitors

Ji-Hu Zhang, Ph.D., Senior Research Investigator, Center for Proteomic Chemistry, Lead Finding Platform, Novartis Institute for Biomedical Research, Inc.

Histone methylation misregulation has been found to be associated with various disorders. Assays for detecting methylation state changes are very useful tools for studying the function of these epigenetic marks. In this presentation, a sensitive homogeneous assay for demethylase activity at the H3K4 site has been developed in a TR-FRET assay format. The assay was validated for lysine-specific demethylase (LSD1) and demonstrated to be suitable for high-throughput screening.

 

2:40 Histone Methyltransferase Inhibitor Selectivity Profiling: Effects of Substrate Choice for in vitro Assays and Comparison to the Results of Cell-Based Assays of Histone Methylation States

Konrad T. Howitz, Ph.D., Director, Epigenetics, Reaction Biology Corporation

In vivo, histone methyltransferases (HMTs) target specific histone lysine or arginine residues at particular locations in chromatin. In vitro assays for HMT inhibitor profiling can be performed with peptides, histone proteins or nucleosomes. To better understand the factors that may make in vitro HMT assays predictive of inhibitor effects in vivo, we are profiling selected compounds by in vitro assays with multiple substrates and by cell-based assays of histone methylation.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Progress Towards Chemical Probes for Epigenetics

Dafydd Owen, Ph.D., Associate Research Fellow, Pfizer, Inc.

Pfizer is a partner in a pre-competitive research collaboration with the Structural Genomics Consortium. This research is focused on the discovery of high-quality chemical probes for emerging targets in epigenetics. These probes will be disclosed publicly and will have no restriction on use. The intention is to provide tools to help understand the potential role, efficacy and safety of targets including those from HMT and HDM classes. Pfizer has programs in both of these areas and will provide an update on our progress.

Cayman Chemical4:15 High Throughput Methods to Study Methyltransferases and SAM-Binding Site Inhibitors

Levi Blazer, Ph.D., Scientist, Molecular Screening, Cayman Chemical

Methyltransferases are attractive drug targets; however assay methodologies for these enzymes are laborious when compared to most high-throughput assays. Cayman Chemical has developed a small molecule fluorescent probe that simplifies high-through-put screening for methyltransferase inhibitors.

Cerep 4:30 The Determination of Epigenetic Target Specificity and Identification of Epigenetics-related in vivo Adverse Drug ReactionsManilduth Ramnath, Ph.D., Project Manager, Custom Services & Innovation, CEREP FranceScreening of 1000 compounds from the BioPrint® database for activity against “writers”, “erasers” and “readers” of the epigenetic code was performed. Resulting in the identification of epigenetic altering compounds as well as the establishment of relationships between the inhibition of specific epigenetic target and known adverse drug reactions associated with these compounds.

4:45 Toward Chemical Probes of Histone Methyltransferases Altered in Cancer

Drew Adams, Ph.D., Research Scientist, Chemical Biology Program, The Broad Institute

Various histone methyltransferases (HMTs) have recently been implicated in cancer and other disease by unbiased genomics studies. We have initiated probe development efforts against several HMTs that appear to be hyperactive in one or more tumor types. Multiple approaches, including the development of biased chemical libraries and high-throughput screening of compounds synthesized at the Broad Institute, have been employed to identify active compounds.

5:15 Harnessing Structure-Based Drug Design to Accelerate Candidate Drug Identification

Philip Fallon, Ph.D., Senior Medicinal Chemist, Domainex, Ltd.

A good supply of PKMT protein is necessary to develop biochemical assays and obtain crystal structures. The expression of domains of interest can be sufficient to enable these activities. Structural biology enables very efficient “hitfinding” by means of our virtual screening approach. Also, utilization of a range of virtual screening strategies increases the likelihood of identifying hits. Finally, the discovery of a new class of small-molecule inhibitors of G9a and GLP will be discussed.

5:45 End of Day

 

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