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Histone deacetylases (HDAC) are a promising target for drug intervention and a number of novel and structurally diverse HDAC inhibitors (HDACi) are being tested at both the pre-clinical and clinical stages. Although, being developed mainly as anti-tumor agents for cancer, many HDACi are now being explored for their efficacy in treating CNS, immunologic, metabolic and inflammatory disorders. However, much remains to be elucidated about the biological functions of HDAC in the cell. The Targeting Histone Deacetylases conference, tracks both the scientific and clinical progress being made in inhibiting histone deacetylases, and highlights the discoveries and tools available to better understand the cellular function of this drug target.
WEDNESDAY, NOVEMBER 2
7:00 am Conference Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Pamela Munster, M.D., Professor, Department of Medicine, University of California San Francisco
8:40 Highly Selective Inhibitors of HDAC6 for the Treatment of Chronic Inflammatory Diseases
Matthew Jarpe, Ph.D., Director of Biological Screening, Biology, Acetylon Pharmaceuticals
Non-selective HDAC inhibitors typically target the Class I HDACs as well as HDAC6. Selective HDAC6 versus selective Class I inhibitors can allow us to differentiate the role of the HDACs in inflammation. Acetylon’s potent, oral, highly selective HDAC6 inhibitors decrease the secretion of pro-inflammatory cytokines from stimulated human macrophages in vitro and demonstrate a significant therapeutic response in animal inflammatory disease models. We expect these compounds will be effective at treating inflammatory diseases while demonstrating a superior safety profile suitable for chronic inflammation due to the absence of Class I HDAC inhibition and its broad epigenetic dysregulation of gene expression.
9:10 Selective Inhibitors of Class IIa HDACs and Their Role in Cell Biology and Inflammation
Michael Nolan, Ph.D., Principal Scientist, Biology, Tempero Pharmaceuticals
We have identified small molecule inhibitors of the Class IIa HDACs that do not inhibit Class I enzymes and used these compounds to evaluate changes in gene expression and T cell biology both in vitro and in mouse models. These first-in-class compounds provide insight to the distinct roles of Class IIa HDACs in cell biology and inflammation.
9:40 Selective Targeting of HDACs in Pediatric Oncology
Olaf Witt, M.D., CCU Pediatric Oncology, German Cancer Research Center
Pediatric cancers differ in many aspects from adult tumors with respect to histology, developmental origin and molecular genetics. Whereas in adult cancers HDACs 1,2,3 are in the focus of current research and drug development, our work in pediatric cancers of neuronal origin has uncovered unexpected expression and function of so far not well studied HDAC family members. Our results point to selective targeting of individual HDACs in a tumor type specific manner.
10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:40 Development of Tetrahydroisoquinoline-Based Hydroxamic Acid Derivatives: Potent HDACi with Marked in vitro and in vivo Anti-Tumor Activities
Wenfang Xu, Ph.D., Professor, Medicinal Chemistry, School of Pharmacy, Shandong University
A novel class of tetrahydroisoquinoline bearing hydroxamic acid derivatives as HDACs inhibitors was designed and synthesized. In vitro activity evaluation of these compounds showed excellent HDACs inhibition and potent growth inhibition in multiple tumor cell lines. Most importantly, relative to SAHA, several derivatives exhibited even more potent in vivo anticancer activities in a human breast carcinoma xenograft model, a human colon tumor xenograft model and a mice hepatoma-22 pulmonary metastasis model.
11:10 Epigenetics Target Profiling – The Tailor-Made Solution for Cellular Epigenetic Selectivity Analysis
Jutta Fritz, Ph.D., Vice President, Business Development, Evotec Munich
To transfer superior preclinical profiles to the clinic, a cellular assay that facilitates meaningful native selectivity profiling of HDAC inhibitors has been developed. Epigenetics Target Profiling delivers detailed information about an inhibitor’s target profile in a physiological context and in the presence of relevant co-factors. It thus allows prediction of off-target liabilities and compound toxicity and helps to reveal HDAC isoforms essential to optimize drug efficacy, thereby providing a rational approach to designing HDACi.
11:40 HDACs in Memory and Cognition: Development of Isoform Selective Inhibitors with Improved CNS Drug Properties
Edward Holson Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard
Deficits in cognition and memory are associated with many disease states including Alzheimer’s disease, Rubinstein Taybi Syndrome and Schizophrenia. Altered acetylation states and the effects on specific gene expression and protein regulation underlie components of CNS disorders. Hypoacetylation states are found in neurological contexts and HDACs offer an attractive target to remedy these altered acetylation states. 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.
12:10 pm Panel Discussion: How Can We Improve Cell and Tissue Selectivity for HDAC Inhibition?
Moderator: Pamela Munster, M.D., Professor, Department of Medicine, University of California San Francisco
Panelists: All speakers from this session.
12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
2:20 Chairperson’s Remarks
2:25 HDAC Inhibition and Knockdown Increase Pluripotency of Human Stem Cells
Paul Sammak, Ph.D., Research Associate Professor, Cell Biology and Physiology, University of Pittsburgh
The HDAC inhibitor trichostatin A (TSA) and siRNA knock down (KD) of HDAC1, 2 and 3 were used to evaluate the role of HDACs for expression of developmental markers and for chromatin organization. TSA and HDAC1, 2 and 3 KD reduced chromatin condensation, histone and DNA methylation. TSA reduced differentiation markers and increased pluripotency markers. HDAC1 and 2 KD increased expression of the conjugate HDAC, while HDAC3 KD did not. Only HDAC3 increased Oct4 expression, a key regulator of pluripotency, suggesting that HDAC3 is a unique target for regulating dedifferentiation and reprogramming.
2:55 Identification of HDAC Substrates and Biomarkers of HDAC Inhibitors Using Proteomics Approach
Yingming Zhao, Ph.D., Associate Professor, The Ben May Department for Cancer Research, University of Chicago
Most substrates for each lysine acetyltransferases and HDACs remain unknown. In addition, LysAc substrates that are responsible for HDAC inhibitors’ anti-tumor sensitivity have not been carefully examined. This knowledge gap needs to be filled to improve our understanding of LysAc in cancer and other diseases. Our group carried out the first two proteomics screenings of lysine acetylation in both mammalian cells and bacterial cells. In this presentation, we will report our current studies on extending this proteomics approach to identifying substrates for LysAc regulatory enzymes and biomarkers.
3:25 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
4:05 Anti-Inflammatory Effects of HDAC Inhibitors in Autoimmunity and Transplantation
Wayne Hancock, Professor, Pathology and Laboratory Medicine, University of Pennsylvania; Chief, Division of Transplant Immunology, Children’s Hospital of Philadelphia
Proof-of-principle studies of the importance of specific HDACs in animal models of autoimmunity and transplantation have provided a rationale to seek isoform-specific and subclass-specific HDAC inhibitors. Several such inhibitors have now been developed and are being evaluated in animal models and using human cells in vitro. Isoform- and subclass-specific HDACi offer considerable potential as anti-inflammatory agents for inflammatory and immunologically-mediated human diseases.
4:35 Metabolism as a Therapeutic Target of HDAC Inhibitors
Tso-Pang Yao, Ph.D., Associate Professor, Pharmacology and Cancer Biology, Duke University
While epigenetics has always been considered the primary therapeutic target of HDAC inhibitors, growing evidence has linked HDAC and protein acetylation to cellular metabolism. The impact of HDAC inhibitors on physiological and tumor metabolism will no doubt become a central issue in their future clinical application. I will discuss the underlying biology of HDAC and metabolic regulation and the potential therapeutic opportunity of targeting metabolic pathways by HDAC inhibitors.
5:05 Interactive Breakout Discussion Groups
6:15 – 7:15 Welcoming Reception in the Exhibit Hall with Poster Viewing
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