Discovery on Target
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Targeting epigenetic modifiers and readers, particularly histone methyltransferases, demethylases and bromodomain-containing proteins have recently set the foundation for a new generation of anti-cancer drugs. Over the past few years, several companies have developed and successfully moved novel compounds targeting EZH2, DOT1L, LSD1, and a collection of BET bromodomain inhibitors into clinical studies. As these compounds continue to progress, developers are now focused on the discovery of new targets and designing novel inhibitors to expand into this robust target space. Of particular interest for discovery are non-BET bromodomain proteins, methyl-lysine readers, arginine methyltransferases, and JmjC-domain containing demethylases.

Cambridge Healthtech Institute has extensively covered the progression of second-generation epigenetic inhibitor discovery and development by establishing the first and longest-running series of meetings specifically focused on enhancing epigenetic drug discovery. We are once again excited to host the industry’s largest drug discovery event focused on targeting the chromatin-modifying enzymes of histone methyltransferases, demethylases and bromodomain-containing proteins. The back-to-back Targeting Histone Methyltransferases and Demethylases and Targeting Epigenetic Readers and Chromatin Remodelers meetings will once again unite academic and industry researchers to discuss novel tools and strategies for targeting these proteins, share the discovery and development of novel inhibitors, and provide updates on preclinical and clinical findings. 

Part 2 - Targeting Epigenetic Readers and Chromatin Remodelers

The second part of this series focuses on one of the most exciting areas of discovery research, 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 many discovery programs initiated, particular interest has been given to targeting the BET family of proteins across a diverse range of therapeutic indications. Widespread efforts have also begun to develop novel chemical matter targeting non-BET bromodomain proteins to assess their therapeutic potential. Most recently, interest and success in developing chemical tools targeting methyl-lysine readers have substantially expanded the possibilities of modulating chromatin states by disrupting epigenetic reading.

Final Agenda


RECOMMENDED ALL ACCESS PACKAGE:

• September 19 Short Course: Phenotypic Screening and Chemical Probe Development

• September 19 Short Course: RNA as a Small Molecule Drug Target

• September 20-21 Conference: Targeting Histone Methyltransferases and Demethylases

• September 21-22 Conference: Targeting Epigenetic Readers and Chromatin Remodelers


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Wednesday, September 21

11:20 am Conference Registration Open

11:25 Enjoy Lunch on Your Own


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


DEVELOPING NOVEL BROMODOMAIN INHIBITORS

3:20 Chairperson’s Opening Remarks

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

3:25 FEATURED PRESENTATION: Bromodomain Chemical Probes to Explore Epigenetic Pathways

Oleg Fedorov, Ph.D., Group Leader, Biophysics and Biochemical Screening, Structural Genomics Consortium and Target Discovery Institute, University of Oxford

The Structural Genomics Consortium (SGC) together with major pharmaceutical companies initiated the program of developing chemical tool compounds for these proteins. We developed more than 30 chemical probes which are released to the academic community without restriction of use. I will highlight the recent progress in the field of bromodomain inhibitors, especially outside the BET subfamily. We achieved a good coverage of the family and identified the potential application in multiple disease areas such as inflammation and osteoporosis.

4:05 Fragment-Based Discovery of Chemical Probes for BRD9

Laetitia Martin, Ph.D., Research Laboratory Head & Project Leader, Medicinal Chemistry, Boehringer Ingelheim

We set out to develop an inhibitor compound targeting the bromodomain of BRD9. The discovery and structure-based optimization of a potent and selective BRD9 bromodomain inhibitor series will be presented. These compounds modulate BRD9 bromodomain cellular function and display anti-tumor activity in an AML xenograft model. Two chemical probes, BI-7273 and BI-9564, were identified that should prove useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.

4:35 Sponsored Presentation (Opportunity Available)

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing

5:40 Inducible Binding Conformations that Enabled the Identification of Selective in vitro Bromodomain Inhibitors from a Common Scaffold

Terry Crawford, Senior Scientific Researcher, Medicinal Chemistry, Genentech, Inc.

Through a fragment screening approach we identified 6-methyl pyrrolopyridone as a highly ligand efficient scaffold. We discovered that lipophilic substitutions on this scaffold directed towards the conserved water network found in the bromodomain binding pocket were able to induce two distinct binding conformations, either through rearrangement of the conserved water network or the formation of a hydrophobic channel directed below the waters. These inducible conformations led to the identification of selectivity handles for BRD7/9, CECR2, and TAF1-BD2.

6:10 FEATURED PRESENTATION: Targeting BET Degradation

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

6:40 End of Day

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Thursday, September 22

7:30 am Registration Open and Morning Coffee


EVALUATING THERAPEUTIC POTENTIAL

8:30 Chairperson’s Remarks

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

8:35 Mechanism-Based Combination Strategies for BET Inhibitors in Solid and Hematologic Cancers

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

BET (bromodomain and extra-terminal) family proteins are transcriptional regulators known to control expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in a number of hematologic and solid tumor cancer models. Data will be presented characterizing the single agent activity, mechanisms of action, and potential combination strategies for GSK525762, a potent and selective pan-BET inhibitor in early clinical development.

9:00 Tumor-Intrinsic and Immune Modulatory Activities of the BET Inhibitor INBC054329

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

9:25 Novel Bromodomain Inhibitors with Broad Activities

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

A collaborative effort between the University of Miami, Epigenetix Inc. and the NeoMed Institute has resulted in the generation of a range of novel bromodomain inhibitors. Some of these molecules showed unexpected efficacy and potency in in vitro and in vivo in cancer models. Notably, unlike reference compounds, these compounds bind to not only the BET bromodomains but also to several other bromodomain-containing proteins. Some of the resulting synergies will be discussed.

9:50 Novel BET Bromodomain Inhibitors to Treat Disease

Christopher Burns, Ph.D., Laboratory Head, ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research

We have identified chemically novel series of BET bromodomain proteins based on a novel benzodiazpine scaffold, that are readily prepared and possess potent activity in cells. Studies to improve their molecular and ADME properties will be presented. We have also explored apoptosis mechanisms involved in BET bromodomain inhibitor activity as well as their potential in osteosarcoma.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:10 BET Bromodomain Inhibitors in Prostate Cancer

Irfan A. Asangani, Ph.D., Assistant Professor, Cancer Biology, Perelman School of Medicine, University of Pennsylvania

BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. Interestingly, AR-variant 7 (AR-v7), which has been reported to be associated with resistance to antiandrogen treatments, was markedly repressed by BET inhibitors. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively.

11:40 FEATURED PRESENTATION: Bromodomain Inhibition of the Transcriptional Coactivators CBP/EP300 as a Therapeutic Strategy to Target the IRF4 Network in Multiple Myeloma

Robert J. Sims III, Ph.D., Vice President, Research, Constellation Pharmaceuticals, Inc.

Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action.

12:10 pm Sponsored Presentation (Opportunity Available)

12:40 Session Break

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:30 Refreshment Break in the Exhibit Hall with Poster Viewing


PREDICTING RESISTANCE AND COMBINATIONS STRATEGIES FOR BET BROMODOMAIN INHIBITORS

2:15 Chairperson’s Remarks

Robert J. Sims III, Ph.D., Vice President, Biology, Constellation Pharmaceuticals, Inc.

2:20 Response and Resistance to BET Bromodomain Inhibitors in Breast Cancer

Kornelia Polyak, M.D., Ph.D., Professor of Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School

Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease that lacks targeted therapy. We found that TNBCs are preferentially sensitive to BET bromodomain inhibition in vitro and in vivo. BET-resistant TNBC cells remained dependent on wild-type BRD4 that supports transcription and proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identified association with MED1 and hyper-phosphorylation of BRD4 due to decreased activity of PP2A that we identified as a principal BRD4 serine phosphatase.

2:50 New BET Inhibitor Combination Strategies and Lessons Learned from Clinical Trials Conducted 25 Years Ago

Jonas Nilsson, Ph.D., Professor, Experimental Cancer Surgery, Surgery, Sahlgrenska Cancer Center, University of Gothenburg

We have found new combination therapies of cancer. We also have strong evidence showing that BET inhibitors were already in Phase II trials in the 1980s. The BETi we disclose is a BD2-selective. During this presentation attendees will learn about the trial results from the first BETi in Phase II. They will also learn about the chemical starting point of BD2-selective BETi.

3:20 Session Break


TARGETING METHYL-LYSINE AND ACETYL-LYSINE READERS

3:25 Chairperson’s Remarks

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

3:30 PHD and YEATS Domains and Their Roles in Epigenetic Mechanisms

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

Plant homeodomain (PHD) fingers and YEATS domains are found in proteins involved in a wide array of fundamental biological processes including transcription, replication, DNA damage repair, cell differentiation and survival. These domains comprise the largest families of epigenetic readers, capable of recognizing PTMs (posttranslational modifications) of histones. Here, we detail the binding mechanisms and biological functions of the readers that select for methylated, acetylated, and unmodified histone H3 tails. We compare the specificities and discuss the significance of crosstalk between PTMs and the consequence of combinatorial readout for the recruitment of these readers to chromatin.

4:00 Targeting Chromatin Regulation via Methyl-Lysine Reader Chemical Probes

Lindsey Ingerman James, Ph.D., Research Assistant Professor, Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

Plant homeodomain (PHD) fingers and YEATS comprise the largest families of epigenetic readers, capable of recognizing PTMs histones. Here, we detail the binding mechanisms and biological functions of the readers that select for methylated, acetylated, and unmodified histone H3 tails. We compare the specificities and discuss the significance of crosstalk between PTMs and the consequence of combinatorial readout for the recruitment of these readers to chromatin.

4:30 Identification and Validation of CBX2 as a Therapeutic Target

Cheryl D. Helgason, Ph.D., Senior Scientist, Experimental Therapeutics, British Columbia Cancer Agency Research Centre

Our studies have identified the chromodomain protein CBX2, an epigenetic reader, as a potential oncogene and therapeutic target in numerous tumor types. In this presentation we will present data demonstrating the identification of CBX2 as an oncogene worthy of targeting. We will also demonstrate that targeting CBX2 in prostate cancer cells results in significant cell death. Future perspectives will focus on attempts to target CBX2, as well as to identify co-interactors that may serve as complimentary therapeutic targets.

5:00 Close of Conference



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Cellecta

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SPONSORSHIPS & EXHIBITS

The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:

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

 

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IPR-Special-Report-Packages  

SEPTEMBER 19 SYMPOSIA:

Next-Generation Histone Deacetylase Inhibitors

Strategies for Tackling Rare Genetic Diseases

Understanding CRISPR: Mechanisms and Applications

Autoimmunity – Small Molecule Approaches

NK Cell-Based Cancer Immunotherapy

CONFERENCES

SEPTEMBER 20-21

Targeting Histone Methyltransferases and Demethylases

Targeting the Ubiquitin Proteasome System

Targeting the Microbiome
– Part 1

GPCR-Based Drug Discovery - Part 1

Advances in Gene Editing and Gene Silencing – Part 1

Gene Therapy Breakthroughs

Antibodies Against Membrane Protein Targets – Part 1

Targeting Cardio-Metabolic Diseases

Targeting Ocular Disorders

SEPTEMBER 21-22

Targeting Epigenetic Readers and Chromatin Remodelers

Kinase Inhibitor Discovery

Targeting the Microbiome
– Part 2

GPCR-Based Drug Discovery - Part 2

Advances in Gene Editing and Gene Silencing – Part 2

Translating Cancer Genomics

Antibodies Against Membrane Protein Targets – Part 2

Metabolomics in Drug Discovery

TRAINING SEMINAR: Data Visualization

SHORT COURSES*

Monday, September 19
8:00 - 11:00 am

(SC1) Immunology Basics for Chemists

(SC2) Designing Peptide Therapeutics for Specific PPIs

(SC3) Phenotypic Screening and Chemical Probe Development

(SC4) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 1

Monday, September 19
2:00 - 3:00 pm

(SC5) GPCR Structure-Based Drug Discovery

(SC6) RNA as a Small Molecule Drug Target

(SC7) Using IP Landscape Studies to Improve Your Confidence

(SC8) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 2

Monday, September 19
3:30 - 6:30 pm

(SC9) Targeting of GPCRs with Monoclonal Antibodies

(SC10) Introduction to Targeted Covalent Inhibitors

(SC11) Contact Lens Drug Delivery Systems

(SC12) Introduction to Gene Editing

Monday, September 19
7:00 - 9:30 pm

(SC13) Convergence of Immunotherapy and Epigenetics for Cancer Treatment

Wednesday, September 21
7:00 - 9:30 pm

(SC14) Cancer Metabolism: Pathways, Targets and Clinical Updates

(SC15) Introduction to Allosteric Modulators and Biased Ligands of GPCRs

(SC16) Functional Screening Strategies Using CRISPR and RNAi

(SC17) Challenges and Opportunities in DNA Methyl Transferase (DNMT) Inhibitors as Therapeutics