2013 Archived Content
Targeting Epigenetic Readers

 

ABOUT THIS CONFERENCE 

The expanse of epigenetic modulators poised as promising therapeutic targets has never been more robust. Yet, until recently, enzymatic modulators of writer and eraser classes have been the main focus of therapeutic development. Over the past few years, a relatively underexplored group of proteins have emerged as promising targets. Operating at the interface of translating histone marks, proteins such as the BET family bromodomain readers have demonstrated favorable activity when inhibited in human cancers. Therapeutic potential is evident, but with little potent and selective chemical matter available for inhibition, the biological consequence associated with disrupting epigenetic reading is largely undefined. Cambridge Healthtech Institute is proud to announce the Inaugural Targeting Epigenetic Readers conference, designed to unite academic and industry researchers for the development of chemical probes to further our understanding of the therapeutic opportunities associated with targeting reader domains.

SUGGESTED EVENT PACKAGE:

 

September 23: Biochemical and Structure-Based Approaches to Epigenetic Drug Discovery Short Course 3 

September 23: Characterization and Quantification of Histone Modifications Short Course 8 

September 24 - 25: Targeting Epigenetic Readers Conference 

September 25 - 26: Next-Generation Histone Deacetylase Inhibitors Conference 

 

Day 1 | Day 2 | Download Brochure | Download Track Brochure 


 

Monday, September 23


 

4:00 - 6:30 pm Early Main Conference Registration


Tuesday, September 24


7:00 am Registration and Morning Coffee


FEATURED SESSION: LEADERS IN EPIGENETIC DRUG DISCOVERY  

8:10 Chairperson’s Opening Remarks

Manilduth Ramnath, Ph.D., Project Manager, Custom Services & Innovation, Cerep

8:15 Drugging the Epigenome

Cheryl ArrowsmithCheryl H. Arrowsmith, Ph.D., Chief Scientist, Structural Genomics Consortium; Professor, Medical Biophysics; Canada Research Chair, Structural Proteomics, University of Toronto

Modulation of epigenetics gene regulation holds great potential for new therapeutic targets in many chronic diseases. We are taking a protein family approach to understand the network of human proteins that deposit, recognize and remove acetyl and methyl marks on histones and non-histone proteins. Using structure-guided medicinal chemistry via a network of collaborators in academia and the pharmaceutical industry we are generating potent, selective and cell-active antagonists of epigenetic regulatory proteins for use in target validation and biological discovery. I will discuss the chemical tractability of these protein families and their potential for new classes of therapeutics.

9:00 Drugging the Epigenome in Cancer

Peter TumminoPeter J. Tummino, Ph.D., Head, Biology, Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline Pharmaceuticals

Over the past several years, there is increasing evidence of epigenetic dysregulation in cancer. The writer, eraser, and reader proteins of histone epigenetic marks have become targets for small-molecule therapeutic intervention. A perspective on both the challenges and opportunities for drug discovery and development against these classes of targets will be presented, exemplifying GSK’s experience with specific targets.

9:45 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


MECHANISTIC INSIGHTS INTO READER-INDUCED TUMORIGENESIS

10:45 Targeting Bromodomains in NUT Midline Carcinoma

Christopher FrenchChristopher A. French, M.D., Assistant Professor, Department of Pathology, Harvard Medical School; Assistant Professor, Pathology, Brigham and Women’s Hospital

I will first discuss the basic clinical aspects of NUT midline carcinoma, including its diagnosis and clinical behavior. I will then discuss two mechanisms by which the causative BRD-NUT oncoproteins appear to block differentiation in this cancer. These include, first, the tethering and sequestration of epigenetic writers, such as p300, to discrete chromatin regions by the dual bromodomains of BRD4 and the binding of NUT to p300; and second, the activation of MYC. I will then discuss how we have therapeutically targeted these mechanisms using HDAC inhibitors and BET bromodomain inhibitors.

11:15 Selected Poster Presentation: Blocking Distinct Surfaces of WDR5 for Histone and RNA Binding Using Genetically Encoded Antagonists

Ankit Gupta, Ph.D., Research Scientist, Biochemistry & Molecular Biology, The University of Chicago

11:45 CHD5 and H3: A Must-Read for Tumor Suppression

Alea MillsAlea A. Mills, Ph.D., Professor & Team Leader, Cold Spring Harbor Laboratory

CHD5 binds unmodified histone 3 (H3) via its dual PHDs, motifs characteristic of 'readers' of epigenetic marks. This interaction is essential for CHD5 to modulate transcription, to inhibit proliferation, and to induce differentiation. Whereas wild type CHD5 inhibits tumor growth, mutations that perturb the CHD5:H3 interaction abolish CHD5's tumor suppressive activity, leading to enhanced tumorigenesis in vivo. Thus, the CHD5:H3 interaction is essential for tumor suppression.

12:15 pm Open Innovation at Pfizer to Identify a Bromodomain Chemical Probe

John Trzupek, Ph.D., MBA, Associate Director, Biotherapeutics, External Chemistry Innovation, Pfizer

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


PROGRESS TOWARDS NOVEL CHEMICAL READER ANTAGONISTS

2:15 Chairperson’s Opening Remarks

Ming-Ming Zhou, Ph.D., Harold and Golden Lamport Professor and Chairman, Department of Structural & Chemical Biology; Co-Director, ExperimentalTherapeutics Institute, Icahn School of Medicine at Mount Sinai

2:20 From Epigenetic Mechanism to Targeted Therapy

Ming-Ming ZhouMing-Ming Zhou, Ph.D., Harold and Golden Lamport Professor and Chairman, Department of Structural & Chemical Biology; Co-Director, ExperimentalTherapeutics Institute, Icahn School of Medicine at Mount Sinai

Gene expression of the human genome in response to physiological and environmental stimuli is dictated by chemical modifications of the DNA and the DNA-packing histones, as well as transcription factors. This highly complex biological system that operates with a large number and different combinations of epigenetic modifications has defied a full investigation of its basic mechanisms. In this talk, Dr. Zhou will present his group’s latest structural and mechanistic study of protein-protein interactions involving key transcription factors as well as core histones that are essential for gene transcriptional activation in chromatin. He will also discuss the functional implications of their new findings of the basic principles that govern the molecular interactions and regulation in gene expression, and a new strategy for developing targeted epigenetic therapy for human diseases including cancer and chronic inflammation.

2:50 Promoting Illiteracy: Inhibition of Methyl-Lysine Readers by Small Molecule Chemical Probes

Lindsey Ingerman JamesLindsey Ingerman James, Ph.D., Research Assistant Professor, Center for Integrative Chemical Biology & Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina

Lysine methylation is a post-translational modification that can be ‘read’ by methyl-lysine recognition domains, of which there are more than 200 in the human proteome, in turn regulating differentiation, development, and gene transcription. I will describe our efforts towards the discovery of UNC1215, a potent and selective chemical probe for the methyl-lysine reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of transcriptional repressors. The potency, specificity, and cellular effects of UNC1215 establish it as the first cell-active methyl-lysine reader antagonist.

Coferon3:20 Targeting Selective Inhibition of BET Proteins by Context Specific Engagement of Tandem Bromodomains with Coferons

Lee Arnold, Ph.D., Vice President & CSO, Coferon Inc.

Coferon's proprietary bioorthogonal chemistries enable self-assembly of large dimeric molecules upon macromolecular targets inside the cell.  BET proteins use tandem bromodomains to bind acetylated histone proteins and direct a wide range of biological responses. BRD4 alone is linked to cancer, immunologic and cardiovascular outcomes, inferring a need for selective therapeutics. We have identified coferons that engage both bromodomains of BRD4 in different spatial orientations in cells, allowing us to probe the effects of selective inhibition.

3:50 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Disrupting the Reader

John DenuJohn M. Denu, Ph.D., Director, Epigenetics Theme, Wisconsin Institute for Discovery; Professor, Biomolecular Chemistry, School of Medicine and PublicHealth, University of Wisconsin

The epigenome is an additional layer of chemical information that acts on top of the genome and informs gene expression. One major type of epigenetic mechanism is the complex post-translational modification (PTM) to histone proteins, which wrap DNA and regulate accessibility for gene expression. The presentation will cover experimental strategies and assay platforms to reveal how protein readers interpret complex PTM language and how this information can be utilized to developed small-molecule disrupters (inhibitors) of readers implicated in disease.

5:00 Histone Binding Mechanisms and Specificities of PHD Fingers

Tatiana KutateladzeTatiana Kutateladze, Ph.D., Associate Professor, Department of Pharmacology, Anschutz Medical Campus, University of Colorado

Plant homeodomain (PHD) fingers comprise one of the largest families of epigenetic effectors capable of recognizing PTMs (posttranslational modifications) of histones. Here, I summarize the structures and binding mechanisms of the PHD fingers that select for modified and unmodified histone H3 tails. I will compare the specificities of PHD fingers, Tudor and other histone readers, and discuss the significance of crosstalk between PTMs and the consequence of combinatorial readout for the selective recruitment of these effectors to chromatin.

5:30 Interactive Breakout Discussion Groups

This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Table 1: Unintended Cellular and Molecular Consequences of Targeting BET Proteins

Moderator: Gerald V. Denis, Ph.D., Associate Professor, Cancer Research Center, Department of Pharmacology & Medicine, Boston University School of Medicine

  • How should we be considering the safety profile of BET inhibitors, in view of the known roles of these proteins as co-repressors as well as co-activators?
  • How worrisome is the theoretical scenario that displacement of BET proteins (Brd2, Brd3, Brd4, Brdt, which are NOT highly selectively distinguished by the available small molecule inhibitors) from one set of loci may lead to unintended transcriptional activation or repression of other loci due to a shift in mass action?
  • BET protein inhibitors or shRNAs appear to act on a wide array of promoters without widespread apoptosis, over-proliferation, whole-body toxicity or gross transcriptional confusion (i.e. Brd2 inhibition is simultaneously pro-adipogenic, anti-inflammatory and anti-proliferative); is this a problem or an opportunity, and what does it tell us about transcriptional networks that are co-regulated by this set of proteins, by analogy to the SWI/SNF-regulated networks?
 

Table 2: Challenges Associated with the Discovery and Characterization of Inhibitors of Methyl-Lysine Reader Domains

Moderator: Lindsey Ingerman James, Ph.D., Research Assistant Professor, Center for Integrative Chemical Biology & Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina

  • What techniques may be most valuable to implement at the hit discovery stage for this relatively unexplored target class?
  • In general, are methyl-lysine reader domains druggable targets? Does modulation of these nonenzymatic proteins have the potential to overcome undruggable genetic changes that drive cancer?
  • How should we best go about characterizing chemical probes for methyl-lysine readers for which there is little known biology, and how valuable are these probes for target validation of such epigenetic regulators?
 

Table 3: Approaches to Meaningful Determinations of Selectivity of BET Inhibitors

Moderator: Lee D. Arnold, Ph.D., Vice President & CSO, Coferon, Inc.

  • Considering that the pursuit of selectivity is primarily to maximize therapeutic benefits and avoid off-target effects, what is the relevant selectivity? BRD2/3/4/T? BD1 versus BD2? Specific monobromodomain targeting? Engagement of a specific configuration of tandem BDs? Selective modulation of a subset of target gene(s)?
  • How is selectivity best determined? Given the overlapping roles, similarities in BET protein structure, conformational freedom, reports of homo- and hetero-dimeric interactions, effects of post-translational modifications, and influence of the dynamic interactome and chromatin modifications in cells, are there meaningful BRD2/3/4/T in vitro selectivity assays?
  • Considering the dominant role of BRD4 in mitosis and transcription, can effects on BRD2, BRD3 and BRDT be quantified cleanly? Are there endpoints in cellular assays reflective of selective BET inhibition? Is global eviction of a BET protein from chromatin useful in determining selectivity? Or should it be compared with displacement from target loci to reflect of the selectivity of an inhibitor? Are there specific genes in certain cell backgrounds that can be used as indicators of specificity?
  • How important is seeking improved BET selectivity? PanBET inhibitors are reported to be efficacious in mouse models without adverse effects, but numerous biological processes are affected. BD1 and BD2 affinities for acetylated peptides differ, and BD1/BD2 selective antagonists have been reported. While these do not achieve selectivity amongst the BET family members, is this sufficient to produce more specific effects and improvements in therapeutic window? What level of redundancy is there between the Brd family members and would cancer cells be able to readily adapt to a selective Brd4 inhibition through compensatory Brd2 (or 3) up regulation? Are undesirable effects (e.g. BRDT inhibition of spermatogenesis) reversible or imprinted
 

 

6:30 Welcome Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Day

 

 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com