Next-Generation Histone Deacetylase Inhibitors header

About This Symposium:

Histone deacetylases (HDACs) have proven to be a promising target for drug intervention and there are a number of HDAC inhibitors (HDACi) currently being tested in pre-clinical and clinical stages. 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 eighth annual event 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.

New HDAC Chemistries and Screening Approaches

8:00 Chairperson’s Opening Remarks

Alan P. Kozikowski, Ph.D., Professor, College of Pharmacy Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago

8:10 HDAC6 Inhibitor Platform: Therapeutic Applications in Charcot-Marie-Tooth (CMT) and Rett Syndrome

Alan P. Kozikowski, Ph.D., Professor, College of Pharmacy Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago

HDAC6 is one of the key enzymes that regulates the acetylation state of the microtubule protein a-tubulin, and microtubule-dependent transport rates are more efficient along acetylated a-tubulin than deacetylated a-tubulin. In addition to facilitating anterograde transport of new cargo to synaptic zones, acetyl-tubulin also increases the ability of damaged organelles or misfolded proteins to leave synaptic zones. This may be very important for Rett Syndrome as well as other conditions, as damaged mitochondria and elevated levels of improperly spliced mRNA transcripts have been noted in MeCP2-deficient neurons. The design, synthesis, assay, and application of HDAC6 inhibitors to various therapeutic areas will be covered.

8:55 Defining the Structural Requirements for the Design of Inter-Class Selective HDAC Inhibitors

Edward Holson, Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research and Director of Chemistry, Chemical Biology Platform, Broad Institute

I will describe the minimal structural requirements necessary for the potent and selective inhibition of HDAC6 achieved through the careful choice of linker element only. We extend these design considerations to the design of the first inhibitors capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our biochemical and computational data provide evidence that evolutionary relationships between HDACs cannot always predict molecular recognition or ligand binding similarities.

9:40 Coffee break

10:00 Engaging Nuclear Receptors for Targeted Histone Deacetylase Inhibition

Adeboyega “Yomi” Oyelere, Ph.D., Associate Professor, School of Chemistry and Biochemistry, Georgia Institute of Technology

Histone deacetylase (HDAC) inhibition is a clinically validated strategy for cancer treatment. Despite promises in preclinical studies, HDAC inhibitors (HDACi) have been less efficacious in treating solid tumors. To address this problem, my lab has designed HDACi equipped with secondary pharmacophores to facilitate selective accumulation in malignant cells. In this presentation, I will discuss the discovery and SAR studies on new class of HDACi compounds targeted to breast and prostate tumors by equipping them with the additional ability to bind to the estrogen receptor (ER) and androgen receptor (AR) respectively.

10:30 Imaging HDAC Density and Drug Inhibition in the Human Brain

Jacob Hooker, Ph.D., Assistant Professor, Radiology, Harvard Medical School

Histone deacetylases have shown broad potential in treatments against cancer and emerging data supports HDAC-targeting in the context of cardiovascular disease and CNS dysfunction. Development of a radiotracer for non-invasive imaging will elucidate the distribution and functional roles of HDACs in human and accelerate medical research and drug discovery in this domain. We have developed an HDAC imaging agent, [11C]Martinostat for imaging HDACs in the brain, heart, kidney, pancreas and spleen to realize these goals.

11:00 Enjoy Lunch on Your Own

Exploring HDAC Biology

12:00 pm 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

12:10 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.

12:40 Characterization of HDAC Inhibitors: From Structural Analysis to Cell Function

Pascal Steiner, Ph.D., Scientist, Department of Neuroscience, Genentech, Inc.

A detailed understanding of how HDAC inhibitors with different pharmacological properties affect biological functions in vitro and in vivo is still missing. I will present our recent findings showing the evaluation of HDAC inhibitors potency in vitro using recombinant proteins and of their pharmacodynamic properties as measured with histone acetylation are insufficient to predict their functional consequences on biological activity such as gene expression and cell viability and therefore might be misleading in identifying useful HDACi.

1:10 Immuno-Modulatory Function of HDAC6 and Tubulin Acetylation

Tso-Pang Yao, Ph.D., Associate Professor, Department of Pharmacology and Cancer Biology, Duke University

HDAC inhibitors show an anti-inflammatory activity. The underlying mechanism is not well understood. The potential toxicity associated with pan-HDAC inhibitors also presents a barrier for their chronic use in inflammatory disease. We will discuss different anti-inflammatory phenotypes induced by HDAC inhibitors and offer mechanistic basis for differential therapeutic effects and opportunities for targeting selective HDAC members. 

1:40 Coffee break

2:00 The Roles of Class I HDACs in Alzheimer’s Disease

Li-Huei Tsai, Ph.D., Professor of Neuroscience, Department of Brain and Cognitive Sciences and Director, Picower Institute for Learning and Memory, Massachusetts Institute of Technology

Impaired genome integrity has been implicated in aging and in neurodegenerative diseases such as Alzheimer’s disease (AD). Our work suggests that the accumulation of DNA damage occurs early in AD pathophysiology, and that this contributed to disease progression. In two separate studies, we found that HDAC1 plays an important role in DNA damage repair and that its reduced activity is correlated with neurodegeneration. Furthermore, HDAC1 may also directly regulate the production and clearance of beta-amyloid. Thus targeting HDAC1 may be beneficial for treatment of neurodegenerative disorders.

2:30 Discrete and Novel Immunologic Roles of Individual Class I HDAC Enzymes

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

In the same way that one size doesn’t fit all, it may not be desirable to try and efficiently block all class I HDAC enzymes. I will present data comparing the differing roles of class I enzymes in the immune system using genetic and pharmacologic approaches. While there is some redundancy and ability to compensate, HDAC1 and HDAC2 play distinct roles and their deletion has differing effects, as does targeting of HDAC3 and HDAC8. Our data point to the potential for major advances in therapeutics if, and as, the ability to target individual class I isoforms is achieved.

3:00 Session Break

Evaluating Pan v/s Isoform-Specific Inhibitors

3:45 Chairperson’s Remarks

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

3:50 Clinical Potential of Isoform Selective HDAC Inhibitors

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

There has been resurgence of activity in developing selective HDAC inhibitors for the clinic. The use of selective inhibitors with genetic models has substantially added to the basic biology of roles for HDACs regulating acetylation states histone and non-histone protein substrates. The potential for ricolinostat, a selective HDAC6 inhibitor, in multiple myeloma, highly selective HDAC6 inhibitors for neurological indications, and targeting HDAC1,2 in β-thalassemia and cellular differentiation in cancer will be discussed.

4:20 HDAC10 Controls Autophagy-Mediated Drug Resistance

Olaf Witt, M.D., Professor for Pediatric Oncology, Hematology and Immunology Head, CCU Pediatric Oncology German Cancer Research Center Head, Section Pediatric Brain Tumors, Department of Pediatric Oncology, Hematology and Immunology, University Children’s Hospital

Pediatric neuronal cancers have been instructive in defining oncogenic functions of HDAC isoforms including HDACs 8, 5 and 9. Recently, we have identified a novel non-epigenetic function of HDAC10 in controlling autophagy-mediated drug resistance. Targeting of HDAC10 inhibits autophagic flux and restores sensitivity of neuroblastoma to chemotherapy. Moreover, high level of HDAC10 expression is associated with poor clinical outcome. We will discuss molecular mechanisms of the HDAC10-autophagy-axis and potential options for isoform selective inhibition.

4:50 Coffee Break

5:10 Targeting HDACs in Cardiovascular Disease

Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Department of Medicine, Division of Cardiology, University of Colorado Denver

Efficacy of small molecule HDAC inhibitors has been demonstrated in animal models of heart failure, where the compounds block cardiac hypertrophy and fibrosis and improve systolic and diastolic function. Since the pharmacological inhibitors used in the pre-clinical heart failure studies target 11 distinct HDAC enzymes, the identity of the HDAC isoform(s) that controls pathological responses of the heart unknown. I will present our recent data from studies of isoform-selective HDAC inhibitors and HDAC knockout mice in models of cardiac disease.

5:40 FEATURED PRESENTATION: Chemical Modulation of Chromatin Structure and Function

JayBradnerJames E. Bradner, M.D., Assistant Professor, Department of Medicine, Harvard University Medical School and Staff Physician, Division of Hematologic Malignancies, Dana-Farber Cancer Institute

With an interest in understanding chromatin-dependent signal transduction to RNA polymerase in developmental and disease biology, we and others have undertaken to discover and optimize small molecule modulators of chromatin regulatory factors. These incisive chemical probes have availed new insights into chromatin structure and function, and suggest plausible translational opportunities for the targeted development of drug-like derivatives in cancer and non-malignant indications. New biotechnologies have been created which allow the rapid identification of critical regulatory regions underlying cell state and which provide the first genome-wide maps of spatial localization of drug molecules within the epigenome. Discussed in this lecture will be mechanistic and translational efforts to modulate gene regulatory pathways of lysine acetylation in cancer transcriptional signaling.

6:30 Close of Symposium

*Separate Registration Required for Next Generation Histone Deacetylase Inhibitors Symposium

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