Histone Deacetylases (HDACs) and Histone AcetylTransferases (HATs) have proven to be promising targets for drug intervention and there are a number of inhibitors currently being tested in both preclinical and clinical stages. New chemistries and screening tools continue to be developed to probe and modify the biology of these emerging drug targets. Cambridge Healthtech Institute’s inaugural conference on Targeting Histone Acetylation, tracks both the scientific and clinical progress being made to better understand the implications of targeting lysine acetylation in histones.

Final Agenda

Thursday, June 11

12:00 pm Registration

PROBING HDAC INHIBITION

2:00 Chairperson’s Opening Remarks

Simon Jones, Ph.D., Vice President Biology and Preclinical Development, Acetylon Pharmaceuticals

2:05 Isoform Selective Histone Deacetylase Inhibitors (HDACi) in Multiple Myeloma (MM)

Simon Jones, Ph.D., Vice President Biology and Preclinical Development, Acetylon Pharmaceuticals

We have explored the role of broad acting and selective HDACi in MM preclinically and in clinical trials, both alone and in combination with novel agents. Broad acting HDACi vorinostat and panobinostat or HDAC 6 selective HDACi ricolinostat have been combined with bortezomib to block aggresomal and proteasomal protein degradation, respectively. Ricolinostat combined with immunomodulatory drugs lenalidomide or pomalidomide downregulate cMyc. We will update the rationale and use of isoform selective HDACi to both increase response and improve tolerability in MM.

2:35 HDAC6 as Master Modulator of Immune-related Pathways

Alejandro Villagra, Ph.D., Assistant Professor, University of South Florida and Scientist, Department of Immunology, Moffitt Cancer Center

Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. Particularly, HDAC6 has been identified to deacetylate numerous non-histone proteins, participating in the regulation of cellular processes such as protein trafficking, aggresome formation, and most recently, as a modulator of immune-related pathways. This opens new possibilities to use selective HDAC6 inhibitors as potential immunomodulatory agents in cancer.

3:05 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 modulating histones acetylation they are recognized as regulators of non-histone proteins. HDAC inhibitors have been used as tool compounds to study basic biology and recognized as promising therapeutics. 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.

3:35 Novel SIRT1-selective Radiotracer Substrate for PET Imaging of Epigenetic Regulation in the Brain

Robin Bonomi, M.D., Ph.D. Student, Department of Biomedical Engineering, Wayne State University  

SIRT1 is known to mediate cleavage of acetyl moiety from acetylated lysine residues of several proteins, including, enzymes of the p53 family, PPARƔ and NF-KB. We developed a novel radiotracer for PET imaging of SIRT1 expression-activity, based on a rationally designed focused library of substrates that have been synthesized and screened for efficacy in vitro in a panel of SIRTs 1-7. The tracer has been validated by dynamic PET/CT imaging studies in rats. 

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

PROBING HDAC INHIBITION (cont’d)

4:45 Novel Approaches to the Discovery of Isoform Selective HDAC Inhibitors

Florence Wagner, Ph.D., Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard

While a number of HDAC inhibitors were discovered over the years, the development of highly potent and isoform selective HDACi is critical not only to refine our understanding regarding the relevant isoform(s) for on-target efficacy but also to mitigate potential mechanism-based, dose-limiting side effects. I will present design strategies that our group has employed towards the discovery of novel HDACi with tuned kinetic (residence time) and thermodynamic binding properties for HDACs 1, 2 and 3.

5:15 The Cardiac Electrophysiological Effects of Pan-HDAC Inhibition

Richard Veenstra, Ph.D., Professor of Pharmacology, SUNY Upstate Medical University, Syracuse, New York  

Prolonged QT interval (LQT) and cardiac arrhythmias account for nearly 20% of all adverse effect drug withdrawals and two of the first four FDA approved HDAC inhibitors carry warnings for LQT/arrhythmia cardiac toxicities. HERG K⁺ channel blockade accounts for >90% of drug-induced LQTs is not strongly indicated for some HDACIs. We will present novel effects of three of these HDACIs on cellular cardiac excitatory ionic currents and electrical coupling of cardiac muscle.   

5:45 Imaging HDAC Density and Drug Inhibition in the Human Brain

Jacob Hooker, Ph.D., Associate Professor, Radiology, Harvard Medical School and Director of Radiochemistry, Martinos Center for Biomedical Imaging, Massachusetts General Hospital

Inhibition of HDACs is being pursued as a therapeutic strategy and yet we do not know for most diseases the relationship between HDAC density or function and disease progression. We have developed an imaging agent, [11C]Martinostat, to quantify HDAC isoforms non-invasively in humans and are using quantitative imaging to determine the relationships between HDAC and disease in the brain and in peripheral organ systems.

6:15 Close of Day

Friday, June 12

TARGETING SYNERGISTIC PATHWAYS

8:35 Chairperson’s Remarks

Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

8:45 Novel Systems Therapeutics Approach to Efficiently Modulate Histone Acetylation

Julen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical Research (CIMA), University of Navarra, Spain

We have proposed and validated a systems therapeutics approach, based on a novel mode of action simultaneously targeting two independent but synergistic pathways: phosphodiesterases (PDEs) and HDACs, that significantly induce histone acetylation. Thus, potent HDAC inhibitors are not required to achieve a remarkable level of histone acetylation; minimizing any potential toxicity related to HDAC inhibition. To validate this novel approach an in vitro and in vivo proof-of-concept, focused on Alzheimer´s Disease, using two known pharmacological compounds, as well as novel first-in-class dual inhibitors, will be presented.

9:15 Immunomodulation and HDAC Inhibitors in Breast Cancer

Pamela Munster, M.D., Professor, Medicine, Program Leader Development Therapeutics; Director, Early Phase Clinical Trials’ Program, Helen Diller Cancer Center, University of California, San Francisco

In previous trials we have shown that HDAC inhibitors modulate estrogen receptor signaling and reverse hormone therapy resistance. One of the steps of acquired hormone therapy resistance is believed to involve upregulation of immune pathways and PD-1 and PD-L1 expression. Several groups have shown a differential regulation of cytotoxic and regulatory T-cells by HDAC inhibitors. We are exploring the role of epigenetic priming to immunotherapy and the differential effects of HDAC inhibitors on T-cells in ER+ breast cancer models and a Phase II clinical trial.

9:45 Selective HDAC Inhibitors in Neurodegenerative Disorders

Elizabeth Thomas, Ph.D., Associate Professor, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute

HDACs have been recognized as potentially useful therapeutic targets for a broad range of neurological disorders. Our findings demonstrate that inhibition of HDAC1 and HDAC3 isotypes can relieve disease phenotypes in Huntington’s disease model systems. Further studies in our lab have focused on identifying gene targets of selective HDAC inhibitors. Overall, the knowledge of gene targets of HDAC inhibitors should help advance these compounds into clinical practice for neurodegenerative disorders.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

UNRAVELING HAT & SIRTUIN BIOLOGY

11:00 CBP/p300/PCAF/GCN5 vs. Tip60/Myst1 in Foxp3+ Treg Biology and Anti-Tumor Immunity

Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

Our work aims to identify post-translational modifications regulating Foxp3 and thereby the development and/or function of Foxp3+ T-regulatory (Treg) cells. Using genetic and pharmacologic approaches, we show that targeting of CBP or p300, and GCN5 or PCAF, diminishes Foxp3 acetylation and Treg suppressive function and promotes anti-tumor immunity, whereas Tip60 targeting induces lethal autoimmunity. Our data provide new insights into the roles of HATs in Tregs, and how these may be targeted for cancer immunotherapy.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Session Break

 UNRAVELING HAT & SIRTUIN BIOLOGY (cont’d)

2:00 Chairperson’s Remarks

Philip Cole, M.D., Ph.D., Professor and Director, Department of Pharmacology and Molecular Sciences, Johns Hopkins University Medical School

2:05 Bioorthogonal Probes to Interrogate Functions of Histone Acetyltransferases

Y. George Zheng, Ph.D., Associate Professor, Department of Pharmaceutical and Biomedical Sciences, University of Georgia

Elucidating biological and pathological functions of protein lysine acetyltransferases (KATs) greatly depends on the knowledge of the dynamic and spatial localization of their enzymatic targets in the cellular proteome. We report the design and application of bioorthogonal chemical probes for facile labeling and detection of substrates of the major human KAT enzymes. This study provides powerful molecular tools for labeling and mapping KAT targets in the context of complex biological mixtures at the proteomic level.

2:35 New Insights into Protein Acetylation from Chemoproteomics

Jordan Meier, Ph.D., Investigator, Chemical Biology Laboratory, and Head, Chemical Genomics Section, National Cancer Institute

A paradox of modern acetylation biology is that while the number of sites of acetylation has climbed rapidly, the number of enzymes thought to catalyze this process has stayed relatively constant. Here we describe the utility of chemical proteomic methods to discover and characterize mechanisms of acetylation in endogenous cellular contexts. Our studies highlight an expanded landscape of lysine acetyltransferases, as well as new strategies to investigate the metabolic regulation and small molecule inhibition of protein acetylation.

3:05 Sirtuin Inhibitors as Anti-Cancer Agents

Hening Lin, Ph.D., Professor, Department of Chemistry and Chemical Biology, Cornell University

Sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. We have discovered several novel enzymatic activities, such as desuccinylation and defatty-acylation, for several sirtuins with no robust deacetylase activity. This has led to the identification of unknown protein post-translational modifications and revealed new biology. It has enabled us to develop compounds that can inhibit particular sirtuins selectively. Some of the selective sirtuins inhibitors can kill cancer cells in cell culture and inhibit tumor formation in mouse models.

3:35 Close of Conference