Archived Content

Next-Generation Histone Deacetylase Inhibitors


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Histone deacetylases (HDACs) have proven to be a promising target for drug intervention and there are a number of HDAC inhibitors (HDACi) being tested in the pre-clinical and clinical stages. HDACi were primarily developed as anti-tumor agents for cancer, but many are now being explored for treating CNS, immunologic, metabolic, inflammatory and cardiovascular disorders. This conference tracks both the scientific and clinical progress being made to better understand the cellular function of HDACs.


7:00 am Conference Registration and Morning Coffee


8:30 Chairperson’s Opening Remarks

Kapil Dhingra, M.D., Managing Member, KAPital Consulting LLC

8:40 HDAC Inhibitors in Oncology – Lessons Learnt and Challenges for the Future

Kapil Dhingra, M.D., Managing Member, KAPital Consulting LLC

Inhibition of HDACs represents a promising avenue for cancer therapeutics and initial success in treating select T-cell lymphomas has led to the FDA approval of two HDAC targeted agents. However, clinical trials over the past decade have also confirmed that broad spectrum HDACi are associated with considerable toxicity and modest efficacy in most common tumor types, especially when used as monotherapy. Hence, a variety of selective and potent HDACi based combinations are being tested, in molecularly defined patient populations.

9:10 Exploiting Target Modulations by HDAC Inhibitors in Solid Tumors

Roberto Pili, M.D., Professor of Oncology and Chief of Genitourinary Section, Leader of the GU Program, Roswell Park Cancer Institute

Epigenetic changes due to histone modifications are associated with tumor initiation and progression. Histone deacetylases have been identified as potential targets for therapeutic interventions in solid tumors. Despite promising pre-clinical data, to date the clinical benefit of single agent HDAC inhibitors has been disappointing. Rationale combinations focused on specific targets may represent a novel strategy to exploit this class of agents. Modulations of specific factors (i.e. HIF, FOXP3) by HDAC inhibition and clinical challenges in drug development will be discussed.

9:40 Radiation Effect Modification through Histone Deacetylase Inhibition

Christopher Barker, M.D., Assistant Attending Physician, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center

Pre-clinical evidence suggests that HDAC inhibition may modulate the biologic effect of ionizing radiation to mitigate the deleterious effects of radiation therapy, while increasing cancer cell radiosensitivity. Retrospective clinical research and early phase clinical trials support the hypothesis that HDAC inhibition may modulate the effects of radiation therapy. Precise mechanisms whereby HDAC inhibitors modulate radiation effects are unknown, but preliminary evidence suggests DNA double-strand break repair may be involved.

10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:40 Targeting Sirtuins for Cancer Treatment: SIRT6 as a Modulator of Tumor Metabolism

Raul Mostoslavsky, M.D., Ph.D., Assistant Professor, The Massachusetts General Hospital Cancer Center, Harvard Medical School 

Proteros 11:10 Kinetics. The Hidden Key to Selective HDAC InhibitorsAdrian Schomburg, Ph.D., Associate Director, Proteros biostructures GmbHClassical approaches for optimization of isotype selective HDAC inhibitors are generally focused on thermodynamic binding properties. Using the Proteros kinetic profiling platform and known equipotent HDAC inhibitors, we have been able to demonstrate significant kinetic selectivity for different HDAC isoforms. This proof-of-concept opened the way for us to identify novel classes of HDAC inhibitors with kinetic selectivity for HDAC2 over HDAC1.

11:40 Clinical Updates on HDACi


Peter Ordentlich, Ph.D., Executive Director, Translational Science & Founder, Syndax Pharmaceuticals

Stefan W. Henning, Ph.D., M.Sc., Senior Project Manager, Development, 4SC AG

Vincent Jacques, Ph.D., Senior Director, Pre-Clinical Development, Repligen Corporation

Kenichi Takeshita, M.D.,Vice President, Clinical R&D, Celgene Corporation

PerkinElmer NEW 200912:40 pm Luncheon Presentation
Development of Efficient Enzymatic and Cell-Based Assays to Monitor Epigenetic Events

Nathalie Rouleau, R&D Senior Section leader, PerkinElmer, Inc.The work presented here describes unique biochemical and cell-based assays for rapid and sensitive detection of HDAC activity. All assays are non-radioactive, using a simple homogenous “add and read” format. For cell-based assays, all steps (cell plating, inhibitor treatment, and detection) were performed directly in culture plates without requirement for washes or protein over-expression. This approach is a significant improvement over existing methods using laborious histone acid extractions, and should accelerate the cellular validation of compounds affecting HDAC activity.

Chemical Design to Improve Efficacy & Safety

2:20 Chairperson’s Remarks

2:25 Development of Isoform Selective Inhibitors for CNS Indications

Edward Holson, Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard

Hypoacetylation states are found in neurological contexts and HDACs offer an attractive target to remedy these altered acetylation states. The development and use of selective inhibitors provides an opportunity to dissect the role of the individual HDAC isoforms and better define their biological functions. We describe our efforts to optimize HDAC inhibitors with greater isoform selectivity, improved CNS drug properties and efficacy in mouse models of learning and memory.

2:55 Hybridization of HDACi for Improved Therapeutics

James Gleason, Ph.D., Associate Professor, Department of Chemistry, McGill University

Therapeutics which regulate gene transcription through nuclear receptors often display enhanced efficacy in the presence of HDACi. We have found that it is possible to take advantage of this synergy by creating bifunctional hybrid molecules which build HDAC inhibition into the structures of nuclear receptor ligands including 1,25-dihydroxyvitamin D3, antiestrogens and retinoic acid analogs. We find that even moderate HDACi activity can significantly enhance antiproliferative activity in a number of cell lines.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Chemical Biology of HDAC Inhibitors

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

Histone deacetylases have been widely recognized as critical regulators of gene and protein function. However, many aspects of HDAC biology are still poorly understood. Small molecule tool compounds offer a complementary approach to genetic approaches to study the function and modulate the active of this important enzyme family.

4:35 2-Aminobenzamide HDAC Inhibitors for Gene Activation in Friedreich’s Ataxia

Joel Gottesfeld, Ph.D., Professor, Department of Molecular Biology, The Scripps Institute

The neurological disorder Friedreich’s Ataxia is caused by heterochromatin silencing of the FXN gene, encoding the essential mitochondrial protein frataxin. We identified 2-aminobenzamide histone deacetylase inhibitors that increase FXN mRNA and protein levels in patient lymphocytes, in neuronal cells derived from patient iPSCs, and in two mouse models for the disease. Pre-clinical studies have been completed and a phase I clinical trial in FRDA patients has been initiated.


5:05 Interactive Breakout Discussion Groups

Challenges with HDAC Inhibitors in the Clinic

Peter Ordentlich, Ph.D., Executive Director, Translational Science & Founder, Syndax Pharmaceuticals

Roberto Pili, M.D., Professor of Oncology and Chief of Genitourinary Section, Leader of the GU Program, Roswell Park Cancer Institute

Do We Need Selectivity or Specificity or Both?

Edward Holson, Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard

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

Defining the Gaps in Our Understanding of HDAC Function

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

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

Topics for discussion:

  • Why does the body have so many HDACs? Is this evidence of massive over-compensation, or are there key pathways linked to specific HDAC subsets or even specific HDAC enzymes?
  • What is the biological function of class IIa HDAC catalytic domains as they do not appear to deacetylate proteins?
  • Catalytic vs. non-catalytic functions of HDACs: Why HDAC knockout mouse phenotypes do not always mimic data with HDAC inhibitors?
  • Should HDAC3 inhibition be avoided based on metabolic phenotypes observed with HDAC3 null mice?
  • How might sub-class or isoenzyme specific inhibitors reach clinical trials, especially in areas beyond oncology?
  • Is the on-target toxicity of class I HDAC inhibitors (e.g., thrombocytopenia) prohibitive for development for indications such as inflammation and heart failure?
  • Can class IIb HDAC targeting using available small molecules give useful biologic potency without the toxicity seen with class I inhibitors?

6:15 – 7:30 Welcoming Reception in the Exhibit Hall with Poster Viewing

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2015 Tracks

September 21

Next-Generation Histone Deacetylase Inhibitors Symposia

Strategies for Rare Diseases Symposia

September 22

Developing CRISPR-Based Therapies Symposia

September 22 - 23

Targeting Epigenetic Readers and Chromatin Remodelers

Targeting the Ubiquitin Proteasome System

Targeting the Microbiome

GPCR - Based Drug Discovery - Part 1

Antibodies Against Membrane Protein Targets - Part 1

RNAi for Functional Genomics Screening

Gene Therapy Breakthroughs

Targeting Ocular Disorders

September 23 - 24

Targeting Histone Methyltransferases and Demethylases

Targeting the Unfolded Protein Response

Kinase Inhibitor Discovery

GPCR-Based Drug Discovery - Part 2

Antibodies Against Membrane Protein Targets - Part 2

New Frontiers in Gene Editing

Quantitative Systems Pharmacology

2015 Short Courses

SC1: Cancer Metabolism: Pathways, Targets and Clinical Updates

SC2: Leveraging Data and Analytics for Drug DiSCovery

SC3: Setting Up Effective Rnai SCreens: From Design to Data to Validation

SC4: Phenotypic SCreening and Chemical Probe Development

SC5: GPCR Structure-based Drug Discovery

SC6: Targeting of GPCRs with Monoclonal Antibodies

SC7: Setting Up Effective Functional SCreens Using 3D Cell Cultures

SC8: Targeting Protein-protein Interactions: Biophysical Approaches

SC9: Preclinical Animal Models for Ocular Indications

SC10: Introduction to Allosteric Modulators and Biased Ligands of GPCRs

SC11: Introduction to Targeted Covalent Inhibitors

SC12: Assays and High-throughput SCreening for Novel Epigenetic Inhibitors

SC13: Gamification and Drug Target Challenges

SC14: A Primer to Gene Editing: Tools and Applications

SC15: Using Mechanistic Physiological Models In Drug Development