The Industry’s Preeminent Event on Novel Drug Targets

ABOUT THIS CONFERENCE 

HDACi were primarily developed as anti-tumor agents for cancer, but many are now being explored for treating neurodegenerative, immunologic, metabolic, inflammatory and cardiovascular disorders. However, much remains to be elucidated about the functional implications of modulating HDACs and understanding the signaling pathways that can cause adverse cellular effects and unwanted toxicity. Cambridge Healthtech Institute's seventh annual conference on Next Generation Histone Deacetylase Inhibitors, tracks both the scientific and clinical progress being made to better understand the cellular function of this complex drug target family.

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Wednesday, September 25

11:50 am Registration

DESIGNING THE IDEAL INHIBITOR 

1:30 pm Chairperson’s Opening Remarks

1:40 PLENARY KEYNOTE PRESENTATION: Towards a Patient-Based Drug Discovery

Stuart L. Schreiber, Ph.D., Director, Chemical Biology and Founding Member, Broad Institute of Harvard and MIT; Howard Hughes Medical Institute Investigator; Morris Loeb Professor of Chemistry and Chemical Biology, Harvard University

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

4:00 FEATURED PRESENTATION: Targeting Lysine Acetylation in Human Disease

James E. Bradner, M.D., Assistant Professor, Department of Medicine, Harvard Medical School   and Investigator, Department of Medical Oncology, Dana-Farber Cancer Institute

Sidechain acetylation of lysine has emerged as a prevalent post-translational modification mediating cell signaling pathways of broad relevance to developmental and disease biology. Our laboratory has focused on the discovery, chemical optimization and clinical translation of small-molecule modulators of acetyl-lysine signaling. This presentation will review the history of lysine acetylation, the development of first and next-generation histone deacetylase inhibitors, as well as the recent development of direct-acting bromodomain inhibitors for cancer therapy. Particular emphasis will be placed on new insights into chromatin biology revealed through the lens of chemical biology, in vitro and in vivo.

4:30 Selective Bioluminescent HDAC Assays for Cell-Based Drug Development

Andrew L. Niles, Senior Research Scientist, Promega Corporation

We are developing a growing suite of selective, bioluminescent, single-addition, deacetylase assays with sufficient sensitivity and robustness for cell-based screening and compound characterization. Here we describe our efforts to define selectivity of these assays using recombinant enzymes, histone deacetylase (HDAC) inhibitors, and cell lines with both overexpressed HDACs and knock down with siRNA.  Selective HDAC inhibition also will be correlated with cellular fate by same-well multiplexing of this assay with viability and cytotoxicity measures.

5:00 Sirtuins: Aging, Diseases and Circadian Control

Leonard P. Guarente, Ph.D., Novartis Professor of Biology, Harvard University

SIR2 and related genes (sirtuins) are NAD-dependent deacetylases that link metabolism, protein acetylation and aging in a variety of species.  Sirtuins are also involved in the longevity conferred by dietary or calorie restriction (CR).  The mammalian sirtuins SIRT1-7 are involved in changes in stress resistance and metabolism that are triggered by CR, which not only extends life span, but also protects against many diseases of aging, including the major neurodegenerative diseases.  In this talk, I will describe how mamamlian SIRT1 impacts tissue maintenance and diseases of aging by deacetyling nuclear transcription factors that govern key physiological pathways.  Moreover, I will also describe new data showing the importance of central circadian control in the brain in mouse longevity studies.  I will also show how SIRT1 mediates circadian control in the brain by deacetylating the central pacemaker BMAL, and demonstrate that this regulation of circadian proteins declines with normal aging in mice.

5:30 Chemogenomic Approaches to Spatiotemporal Regulation of HDAC Activity

Ralph Mazitschek, Ph.D., Assistant Professor, Center for Systems Biology, Chemical Biology Platform, Massachusetts General Hospital

HDACs are master regulators of chromatin structure and function. Beyond controlling the acetylation state of histones they are widely recognized as regulators of non-histone proteins. HDAC inhibitors have been used as tool compounds to study basic biology and recognized as promising therapeutics for the treatment of cancer and beyond. However, systemic exposure is often not well tolerated, or does not provide the required resolution in biological model systems. To address these shortcomings we have developed a new approach to control HDAC activity with greater spatial and temporal resolution.

6:00 Novel Lysine Acylation Pathways and Acetylation-Independent Mechanisms of HDACs

Yingming Zhao, Ph.D., Professor, The Ben May Department for Cancer Research, University of Chicago

We have previously identified several new lysine acylation pathways: lysine propionylation, lysine butyrylation, lysine crotonylation, lysine malonylation, and lysine succinylation. In this presentation, we will report the identification and characterization of the regulatory enzymes that can modulate status of these PTMs. We will also report proteomics screenings that identify the substrates for the new lysine acylations and their regulatory enzymes. Our data suggest that acetylation-independent assays should be used for developing next-generation isoform-specific inhibitors for some HDAC family members.

6:30 Close of Day

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