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One of the most recent and exciting areas of discovery research centers around targeting chromatin modifying proteins, particularly those responsible for the recognition of the histone code written in acetyl and methyl marks. With several clinical trials underway, and discovery programs initiated throughout the biopharma landscape, particular interest has been given to targeting the bromodomain family of proteins across a diverse range of therapeutic indications. Advances in inhibitor development - allowing for individual and polypharmacological targeting of bromodomain proteins, as well as preclinical and clinical studies, are providing a better understanding as to the significant therapeutic potential of targeting chromatin-associated proteins.

Cambridge Healthtech Institute's third annual Targeting Epigenetic Readers and Chromatin Remodelers meeting will once again unite academic and industry researchers for the development of chemical probes, to discuss advances in preclinical and clinical programs, and ultimately to further our understanding of the therapeutic opportunities associated with targeting reader domains and chromatin remodelers.

Final Agenda


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Tuesday, September 22

7:00 am Registration and Morning Coffee


DEVELOPING NOVEL BROMODOMAIN INHIBITORS

8:00 Chairperson’s Opening Remarks

Dafydd Owen, Ph.D., Associate Research Fellow, Medicinal Chemistry, Biotherapeutics Worldwide R&D, Pfizer

8:10 New Chemical Tools Targeting BET Bromodomains and Advances in the Bump and Hole Approach

Alessio Ciulli, Ph.D., Associate Professor & Principal Investigator, Chemical & Structural Biology, College of Life Sciences, University of Dundee

In my talk I will present recent developments from our lab at targeting BET bromodomain proteins using chemical tools, including advances and optimization of our bump and hole approach to introduce controlled selectivity of BET bromodomain chemical probes.

8:40 Specific BET Bromodomain Inhibitors to Treat Disease

Chris Burns, Ph.D., Laboratory Head, Chemical Biology Division, Walter and Eliza Hall Institute, Australia

We have identified chemically novel scaffolds that bind to bromodomain proteins. We prepared a series of compounds based on these chemical scaffolds and profile the compounds for both bromodomain inhibition and activity against AML, to generate compounds with improved selectivity compared to known inhibitors.

9:10 Targeting Gene Expression: Selective vs. Promiscuous Bromodomain Inhibition

Panagis Filippakopoulos, Ph.D., Principal Investigator, Bromodomains, Structural Genomics Consortium & Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford

I will present our efforts to identify novel inhibitors of BRDs that are site selective (in the case of BET bromodomains) as well as our efforts to destroy selectivity while retaining affinity outside the BET family (i.e., promiscuous inhibitors). I will be covering the development and characterization of these tool compounds as well as their properties targeting gene expression in diverse cellular systems, seeking to validate BRD function.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Fragment-Based Design of Potent and Selective CREBBP Bromodomain Ligands

Amedeo Caflisch, Ph.D., Professor and Chair, Computational Structural Biology, Department of Biochemistry, University of Zurich

We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughput docking with a hit rate of 12%. Guided by the docked pose and molecular dynamics simulations, one of the two hits was improved by medicinal chemistry into a low nanomolar lead with very good ligand efficiency and selectivity as measured by isothermal titration calorimetry. The crystal structures of a nanomolar derivative has validated the pose of the hit obtained in silico. Some of the derivatives inhibit proliferation of a small subset of leukemia cell lines.

10:55 Design and Development of Novel BET Bromodomain Inhibitors

Shaomeng Wang, Ph.D., Director, Center for Discovery of New Medicines; Warner-Lambert/Parke-Davis Professor, Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center

I will discuss the design, synthesis, characterization and development of novel small molecule drugs targeting bromodomain-containing proteins for the treatment of human cancer.

11:25 Novel Chemical Probes Targeting Bromodomains

Dafydd Owen, Ph.D., Associate Research Fellow, Medicinal Chemistry, Biotherapeutics Worldwide R&D, Pfizer

During this lecture I will discuss how a small molecule, PFI-3, dissected knock down studies and truly identify the target required for efficacy drugging SWI/SNF mediated cancers. I will also discuss PFI-4, which is a new probe for the bromodomain BRPF1. Finally I will share the development of a new probe, PFI-5, an extension to our PFI-3 story.

PTM Biolabs11:55 Presentation to be Announced

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing


EMERGING PRE-CLINICAL PROGRAMS

1:50 Chairperson’s Remarks

Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor & Associate Dean, Therapeutic Innovation, Miller School of Medicine, University of Miami

2:00 CNS Effects of BET Bromodomain Inhibitors

Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor & Associate Dean, Therapeutic Innovation, Miller School of Medicine, University of Miami

We have developed novel small molecules, such as EP11313, with characteristics of CNS active drugs. These compounds have to date primarily been tested in various models of glioblastoma. However, they have also been useful in demonstrating a role for BET bromodomain proteins as novel epigenetic regulators of cocaine-induced behavioral plasticity.

2:30 Discovery of Scaffold/Platform for the Development of Dual PI3K/BRD4 Inhibitors

Donald Durden, M.D., Ph.D., Professor, Vice Chair, Pediatrics, University of California, San Diego School of Medicine; CEO and President, SignalRx Pharmaceuticals

Key in vitro and animal proof-of-concept efficacy studies will be presented for the lead compound SF2523. Moreover, the recently described epigenetic kinome adaptation response which encodes targeted therapeutic resistance in cancer is blocked by Brd4 BET inhibitors and represents a novel strategy to augment antitumor effects of targeted therapies including PI-3 kinase inhibitors in vitro and in vivo.

3:00 Sponsored Presentation (Opportunity Available)

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Winner Announced


MOLECULAR MECHANISMS IN CANCER

4:10 Synthetic Lethal Approaches to ARID1A-Mutated Ovarian Cancers

Rugang Zhang, Ph.D., Associate Professor, The Wistar Institute

The Zhang laboratory strives to uncover novel epigenetic strategies for developing cancer therapeutics. Recent work from his laboratory will be presented that investigates the molecular basis and therapeutic opportunities for human cancers with mutations in the components of the SWI/SNF chromatin-remodeling complex.

4:40 Discovery of Cancer Drug Targets by CRISPR-Cas9 Screening of Protein Domains

Junwei Shi, Research Scientist, Vakoc Lab, Cold Spring Harbor Laboratory

CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. To improve CRISPR-Cas9 performance in genetic screening, we target CRISPR-CaS9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

5:10 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.

Enhancing Bromodomain Inhibitor Discovery

Moderator: Amedeo Caflisch, Ph.D., Professor and Chair, Computational Structural Biology, Department of Biochemistry, University of Zurich

  • Non-BET bromodomains: Any (strong) evidence for pharmaceutical relevance?
  • Reliability and reproducibility of binding assays for bromodomains; artifacts and false positives of competition binding assays; false negatives of thermal shift assay
  • How to improve stability of bromodomains that are difficult to handle, e.g., ATAD2
  • Practical suggestions for growing crystals of "difficult" bromodomains
  • Cellular assays to demonstrate target engagement

Examining the Basic Actions of BET Proteins

Moderator: Norman C.W. Wong, M.D., FRCP, CSO & Co-Founder, Resverlogix

  • Actions of BET proteins and specifically BRD4 in mediating actions of Pol II that differentiates it from BRD2/3 activity
  • Actions of BET proteins in selective vs. pan inhibition
  • Actions of BET proteins in inflammation

Clinical Considerations for Targeting Bromodomains

Moderator: Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

  • Identification of predictive biomarkers of BET response. What has been the progress and where are we going in the clinic?
  • Combination studies: Much has been published, but what are the best opportunities and underlying mechanisms of action?
  • Do bromodomain-1 or bromodomain-2 specific inhibitors provide advantages over pan-BET bromodomain inhibitors?
  • What advantages do ‘next-generation’ pan-BET inhibitors provide?
  • What are the best opportunities for BET inhibitors in solid tumors? Again, much has been published, but what really stands out from a clinical perspective? Related to this, what are clinically tolerable doses of BET inhibitors?
  • What are the most interesting opportunities for BET inhibitors in non-oncology indications, if any? Related to this, what are the clinical dose-limiting toxicities of BET inhibitors and how does this limit with non-oncology indications?

6:10 Welcome Reception in the Exhibit Hall with Poster Viewing

7:15 Close of Day

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Wednesday, September 23

7:30 am Registration and Morning Coffee


EVALUATING THERAPEUTIC POTENTIAL

8:00 Chairperson’s Remarks

Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

8:10 Inhibition of BET Bromodomain Proteins in Solid Tumors

Anastasia Wyce, Ph.D., Investigator, R&D Oncology, GlaxoSmithKline

We hypothesized that BET inhibitors will similarly regulate expression of MYC family genes (MYC, MYCN, MYCL1) in solid tumor models characterized by MYC family amplification or over-expression. In the current study, we describe the activity of GSK BET inhibitors (I-BETs) in various pre-clinical solid tumor models and discuss the role of MYC gene silencing in the observed phenotypes.

8:40 Preclinical Activity of a Novel BET Bromodomain Inhibitor

Phillip Liu, Ph.D., Associate Directory, Applied Technology, Incyte Corporation

BET bromodomain proteins are epigenetic readers that have been implicated in the development and progression of various diseases including cancer and inflammation. I will present data describing a novel clinical compound INCB54329 that potently and selectively inhibits BET proteins. Activity of INCB54329 in pharmacological models of cancer as single agent and in combination with approved and novel agents will be discussed.

9:10 Efficacy of BET Bromodomain Inhibition in Hematological Tumor Models

Bernard Haendler, Ph.D., Principal Scientist, Global Drug Discovery, Bayer Pharma AG

A novel BET inhibitor with strong in vitro and in vivo efficacy in acute myeloid leukemia, multiple myeloma and lymphoma models will be presented.

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Targeting Hematologic Malignancies with the BET Bromodomain Inhibitor CPI-0610

Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

The BET family of proteins control the expression of key oncogenic pathways through its regulation of RNA polymerase II transcript elongation. CPI-0610 is a potent and selective BET bromodomain inhibitor currently in phase 1 clinical trials for diverse hematologic malignancies. Interim clinical findings from these phase 1 studies will be discussed along with our refined patient selection strategies.

10:55 BET Proteins; Selective and Pan-Inhibition for Treating Human Diseases

Norman C.W. Wong, M.D., FRCP, CSO & Co-Founder, Resverlogix

Our studies of BET inhibitors began with compounds that selectively inhibited the activity of BD-2 for reduction of cardiovascular risks. The lead candidate has been tested in clinical trials involving almost 1000 patients enrolled in the various trials from phase 1a to 2b. Our studies have also expanded to scaffolds that are pan bromodomain inhibitors which appear to be useful other human diseases.

11:25 Enjoy Lunch on Your Own

12:55 pm Plenary Keynote Program:

PLENARY KEYNOTE INTRODUCTION:
Comprehensive Kinase and Epigenetic Compound Profiling

Kelvin LamKelvin Lam, Ph.D., Director, Strategic Partnerships, Reaction Biology Corporation

Kinase inhibitors can be used as chemical probes to understand signal transduction pathways. Since the majority of kinase probes inhibit multiple kinases, understanding the off-target effects will allow scientists to design better poly-pharmacologic compounds to meet specific therapeutic needs. Profiling a compound against the entire kinase gene family will allow us to understand the compound’s full enzymatic activities. Unexpected activities could lead to different chemical design and possibly novel therapeutic opportunities. Reaction Biology offers large-scale in vitro kinase and epigenetic profiling services for (1) compound prioritizing and (2) elucidating novel activities for kinase and epigenetic inhibitors.

PLENARY KEYNOTE SPEAKER:
iPS Cell Technology, Gene Editing and Disease Research

Rudolf JaenischRudolf Jaenisch, M.D., Founding Member, Whitehead Institute for Biomedical Research; Professor, Department of Biology, Massachusetts Institute of Technology

The development of the iPS cell technology has revolutionized our ability to study human diseases in defined in vitro cell culture systems. A major problem of using iPS cells for this “disease in the dish” approach is the choice of control cells because the unpredictable variability between different iPS / ES cells to differentiate into a given lineage. Recently developed efficient gene editing methods such as the CRISPR/Cas system allow the creation of genetically defined models of monogenic as well as polygenic human disorders.

PLENARY KEYNOTE SPEAKER:
The Evolutionary Dynamics and Treatment of Cancer

Martin NowakMartin Nowak, Ph.D., M.Sc., Professor, Biology and Mathematics and Director, Program for Evolutionary Dynamics, Harvard University

Cancer is an evolutionary process. Cancer initiation and progression are caused by somatic mutation and selection of dividing cells. The mathematical theory of evolution can therefore provide quantitative insights into human cancer.

2:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:25 Close of Conference



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SPONSORSHIPS & EXHIBITS

The exhibit hall was sold out in 2014, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2015, contact:

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


 
 

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 

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