Cambridge Healthtech Institute’s inaugural conference on New Tools for Functional Epigenetics Screening focuses on the most innovative tools, assays, models and biomarkers that are being developed for screening a wide variety of DNA and histone modifications. Most of the work being done focuses on the screening of bromodomains, histone deacetylases, histone demethylases, histone methyltransferases, histone acetyl transferases and DNA methyl transferases for oncology indications.
Day 1 | Day 2 | Safety/Screening Brochure | Speaker Bios
Thursday, May 22
11:00 am Registration
12:50 pm Chairperson’s Opening Remarks
Chair: Jatinder Singh, Ph.D., Principal Scientist, Drug Safety and Metabolism, AstraZeneca Pharmaceuticals
1:00 Safety Considerations for Developing Epigenetic Drugs
Jatinder Singh, Ph.D., Principal Scientist, Drug Safety and Metabolism, AstraZeneca Pharmaceuticals
Pharmacological modulators of epigenetic targets are being evaluated for the treatment of both oncology and non-oncology disease indications. This novel paradigm for drug development is associated with unique safety considerations such as transgenerational effects. These will be discussed in the context of current knowledge of epigenetic modulation. Practical recommendations for preclinical safety strategies for epigenetic drug discovery and development programs will be discussed.
1:30 3D Chromatin Organization as a Novel Indicator in Drug Safety Assessment
Jian Tajbakhsh, Ph.D., Program Leader, Translational Cytomics; Head, Chromatin Biology Laboratory, Cedars-Sinai Medical Center
Off-target global DNA demethylation by epigenetic drugs could lead to unwanted cryptic DNA methylation toxicity and carcinogenesis by influencing chromatin conformation, genome organization and gene expression programs. Utilizing high-content and high-throughput 3D image-cytometry of epigenetic marks, the higher-order chromatin organization can be used as an indicator for the causal assessment of global DNA demethylation and heterochromatin decondensation in drug-treated cells towards associated risks such as cytotoxicity and genomic instability.
2:00 High-Content Phenotypic Screening for Novel Inhibitors of Pathological Cardiac Hypertrophy
Brian G. Reid, Ph.D., Director, High Throughput and High Content Screening Core Facility; Research Assistant Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver
Cardiomyocyte hypertrophy is a hallmark of diastolic heart failure, also known as heart failure with preserved ejection fraction (HFpEF). There are a host of cellular pathways that can contribute to pathological cardiac hypertrophy, including epigenetic influences such as HDAC activity. We have developed an in vitro high-content phenotypic assay for cardiomyocyte hypertrophy in primary myocytes that simultaneously monitors multiple phenotypic parameters in a pathway agnostic approach to the discovery of novel therapeutic strategies for the treatment of HFpEF.
2:30 Preclinical Safety Assessment of Epigenetic Drugs: A Practical Perspective
Paul Vancutsem, D.V.M., Ph.D., Senior Director, Toxicology and DMPK, Constellation Pharmaceuticals
Epigenetic mechanisms are`pivotal to the differentiation of cells during development and adulthood. Therefore, drugs developed in oncology and primary care to target these pathways challenge the toxicologist to re-examine accepted paradigms of risk assessment and management. This talk reviews known phenotypes associated with epigenetic imbalances and the timing of their occurence in the context of current guidelines, accepted preclinical study designs and common clinical precautions.
3:00 Refreshment Break in the Exhibit Hall with Poster Viewing
Chair: Paul Vancutsem, D.V.M., Ph.D., Senior Director, Toxicology and DMPK, Constellation Pharmaceuticals
3:45 A High Information Cell-based Assay Platform to Assess Synergistic Combinatorial Effects of the Potent and Selective EZH2 Inhibitor EPZ-6438 (E7438) in Non-Hodgkin Lymphoma
Alejandra Raimondi, Associate Director, Lead Discovery Cell-based Assay Group, Epizyme Inc.
EZH2 is a histone methyltransferase implicated in many cancers and with misregulated enzyme activity in a subset of germinal center B cell non-Hodgkin lymphomas (NHL) that provides a clear and promising path for drug development. Results from our high-quality in vitro combination platform performed in mutant bearing EZH2 cells have shown that the single agent activity of our development candidate EPZ-6438 was strongly enhanced when combined with all components of the CHOP chemotherapy regimen. Interestingly the synergistic effect observed with glucocorticoid receptor agonists, prednisolone and dexamethasone, extended to cell lines with wild type EZH2.
4:15 Interrogating the Bromodomain Family through Chemical Biology
Laura Zawadzke, Ph.D., Principal Research Scientist, Constellation Pharmaceuticals
Readers of histone acetylation include the bromodomain family. Proteins which contain bromodomains often include other reader domains or chromatin-modifying enzyme functions. It is hypothesized that selective inhibitors of bromodomains will find utility in not only basic research of this emerging protein/protein interactions class, but also towards disease amelioration. This talk describes a biochemical approach taken by a Constellation and Genentech collaboration towards identifying selective small molecule inhibitors as probe molecules. Through a platform screening approach, potent and selective bromodomain probes have been identified.
4:45 High-Throughput Assays for Readers and Writers of Histone Methylation
Brandi M. Baughman, Ph.D., Postdoctoral Research Associate, Center for Integrative Chemical Biology and Drug Discovery, The University of North Carolina at Chapel Hill
Readers and writers of histone methylation are important regulators of cellular differentiation and development and are increasingly being implicated in numerous disease states. Small molecules that disrupt interactions between these regulators and chromatin would enable a systematic study of histone regulators and could potentially reveal novel targets for drug discovery. Our group implements several high-throughput assays for screening small molecule modulators of histone methylation. These assays span various technologies to target both readers and writers of histone methylation.
5:15 Kinetic Characterization of Inhibition of Histone Deacetylase by Isoform Specific Inhibitors
Yan-Ling Zhang Ph.D., Director, In Vitro Pharmacology Therapeutics Platform, Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT
Histone deacetylases (HDACs) play a critical role in the modulation of chromatin topology and the regulation of gene transcription. Deregulation of their activity has been implicated in many diseases including cancer, diabetes and psychiatric disorders. Significant efforts have been made to identify selective HDAC inhibitors with unique inhibition kinetics to understand the requirements for on‐target efficacy and mitigate side effect. A highly quantitative microfluidic capillary electrophoresis assay was developed to characterize inhibition kinetics and selectivity of newly developed HDAC inhibitors.
5:45 Q&A with Session Speakers
6:15 Close of Day
Day 1 | Day 2 | Safety/Screening Brochure | Speaker Bios