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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 1 - Targeting Histone Methyltransferases and Demethylases

The first part of this series focuses on targeting the histone methylome as a therapeutic strategy. Adding to the more established series of histone methyltransferase inhibitors, histone demethylase inhibitors have also advanced into clinical studies and are now showing favorable outcomes. Notably, recent interest and success in developing inhibitors against arginine methyltransferase enzymes, JmjC domain demethylases and lysine-methyl readers have substantially deepened the possibilities of regulating chromatin environments via histone methylation.

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


Day 1 | Day 2 | Download Brochure


Tuesday, September 20

7:00 am Registration Open and Morning Coffee


DISCOVERY AND DESIGN OF NOVEL LYSINE DEMETHYLASE INHIBITORS

8:05 Chairperson’s Opening Remarks

Xiaodong Cheng, Ph.D., Professor, Department of Biochemistry, Emory University

8:10 KEYNOTE PRESENTATION: PROBING THE FUNCTIONS OF HISTONE DEMETHYLASES

Chris Schofield, Ph.D., Head, Organic Chemistry, Chemistry Research Laboratory, University of Oxford

Two families of oxidative enzymes catalyzing histone demethylation have been defined – the LSD and JmjC demethylases (KDMs). The lecture will discuss efforts to assign functions to the KDMs (and related enzymes), at biochemical, cellular, and whole organism levels, employing genetic, biochemical and chemical methods. Challenges in the field will be highlighted including with respect to medicinal targeting of KDMs.

8:50 Structure-Based Approaches to Identify Novel and Specific Inhibitors for Different Subfamilies of Jumonji Demethylases

Udo Oppermann, Ph.D., Professor, Molecular Biology; Director, Molecular Laboratory Sciences, Botnar Research Centre; Principal Investigator, Epigenetics and Metabolism, Structural Genomics Consortium, University of Oxford

Inhibitor development has been hampered by structural information and identification of novel chemotypes. We here present a fragment screening approach combining high-throughput structure determination (based on >200 novel ligand complexes) and functional profiling (for chemotype prioritisation) against four subfamilies of human histome demethylases (KDM3, 4, 5, 6) leading to identification of novel chemotypes that were used to generate novel, selective inhibitors.

9:20 Structure, Kinetics and Inhibition of KDM5A, a Key Drug Target in Histone H3 Lysine 4 Demethylation

Xiaodong Cheng, Ph.D., Professor, Department of Biochemistry, Emory University

KDM5 is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). We demonstrated that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of KDM5 enzymes. Making use of the minimal catalytic domain constructs, I will discuss the structure, kinetics, and inhibition of KDM5A.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:35 Jumonji Inhibition Affects Multiple Disease Pathways

Elisabeth Martinez, Ph.D., Assistant Professor, Pharmacology, University of Texas Southwestern Medical Center

Jumonji histone demethylases are deregulated in multiple disorders including cancer and control transcriptional patterns. Here, I will discuss our findings on the impact of pharmacological inhibition of these enzymes on multiple cellular pathways across various cancer types. We find that Jumonji inhibition affects surprising biological cascades beyond transcription including hedgehog signaling and translation efficacy.

11:05 Targeting Histone Lysine Methylation for Cancer Therapy

Yongcheng Song, Ph.D., Associate Professor, Department of Pharmacology, Baylor College of Medicine

Despite still being in an early stage, discovery and development of histone methylation modulators have been growing rapidly in the past few years. We are particularly interested in histone H3 lysine 79 (H3K79) methyltransferase DOT1L, lysine specific demethylase 1 (LSD1), and mutations of isocitrate dehydrogenases (IDH), which are drug targets for several types of cancer. Efforts in the discovery and development of potent small molecule inhibitors and their preclinical activity testing are presented.

11:35 Characterization of a Novel LSD1 Inhibitor in Preclinical Models of Cancer

Sang Hyun Lee, Ph.D., Principal Scientist, Pharmacology, Incyte Corporation

LSD1 is an epigenetic eraser that has been implicated in the development and progression of various cancers. INCB059872 is a potent and selective LSD1 inhibitor. This presentation will focus on the characterization of INCB059872 in preclinical models of cancer, both as a single agent and in combination with standard of care and other novel agents.

12:05 pm Screening for Modulators of Methylation and Demethylation Using Bioluminescent Homogenous Detection Assays

Hicham Zegzouti, Ph.D., Senior Research Scientist, Research and Development, Cellular and Biochemical Technologies, Promega Corporation

Because of the implication of methylation in cancer and other diseases, methyltransferases and demethylases have become validated drug targets. To facilitate the identification of selective and potent inhibitors of these enzymes for drug discovery and as basic research tools, we developed bioluminescent assays for all methyltransferases and JmjC demethylases based on SAH and succinate detection, respectively.

12:35 Session Break

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

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing


DISCOVERY AND DEVELOPMENT OF NOVEL LYSINE METHYLTRANSFERASE INHIBITORS

2:05 Chairperson’s Remarks

Masoud Vedadi, Ph.D., Principal Investigator, Molecular Biophysics, Structural Genomics Consortium; Assistant Professor, Department of Pharmacology and Toxicology, University of Toronto

2:15 Substrate Specificity of Histone Methyltransferases

Masoud Vedadi, Ph.D., Principal Investigator, Molecular Biophysics, Structural Genomics Consortium; Assistant Professor, Department of Pharmacology and Toxicology, University of Toronto

Here we will discuss substrate specificity of histone methyltransferases with a focus on contribution of multiple methyltransferases to methylation of specific histone marks such as H3K4, H3K9 and H4K20. We will also present the latest progress in our quest for discovery of potent, selective and cell active inhibitors of HMTs.

2:45 Targeting Protein Methyltransferases via Novel Models of Interaction

Minkui Luo, Ph.D., Associate Member & Associate Professor, Chemical Biology Program, Memorial Sloan Kettering Cancer Center

In contrast to genetic perturbation small-molecule inhibitors can act via distinct modes of interaction (MOI) and thus lead to different outcomes even if being designed against the same target. My laboratory leveraged multiple approaches to identify PMT inhibitors with novel MOI. Our sinefungin analogues are SAM-competitive inhibitors with the potency and selectivity for multiple PMTs. Our SET8 inhibitors covalently modify the target. The selectivity of these PMT inhibitors largely stems from their abilities to target the distinct conformations.

3:15 Sponsored Presentation (Opportunity Available)

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:25 Fragment-Based Discovery of WDR5-MLL1 Disruptors

Shaun Stauffer, Ph.D., Research Assistant Professor, Pharmacology; Associate Director, Medicinal Chemistry, Vanderbilt University

Fragment-based screening methods coupled with X-ray crystallography offer the potential for rapid optimization of high-affinity ligands for target protein. We have utilized this approach to afford small molecule disruptors of the WDR5-MLL1 complex with subnanomolar affinity.

4:55 Discovery of Selective Inhibitors for Protein Methyltransferases

Jing Liu, Ph.D., Assistant Professor, Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai

Selective small-molecule inhibitors of PMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. To create high-quality selective inhibitors of HMTs, our lab has taken a systematic approach by targeting the HMT substrate binding groove, cofactor binding site, and potential allosteric binding site. This presentation will focus on our recent research progresses on the PMT projects related to type I PRMTs, G9a/GLP, and SETD8.

5:25 Welcome Reception in the Exhibit Hall with Poster Viewing

6:25 End of Day

Day 1 | Day 2 | Download Brochure


Wednesday, September 21

7:30 am Registration Open and Morning Coffee


ASSESSING THE THERAPEUTIC POTENTIAL OF LYSINE METHYLTRANSFERASE INHIBITORS

8:00 Chairperson’s Opening Remarks

Dominique Verhelle, Ph.D., MBA, Strategic Advisor, Third Rock Ventures

8:10 FEATURED PRESENTATION: The EZH2 Inhibitor Tazemetostat as a Potential Therapeutic for Non-Hodgkin Lymphoma and Genetically Defined Solid Tumors

Jesse Smith, Ph.D., Vice President, Biological Sciences, Epizyme

This presentation will include a discussion of the current model for tazemetostat’s mechanism-of-action in NHL, based upon emerging preclinical, translational and clinical data. Additionally, the therapeutic potential of tazemetostat in genetically defined solid tumors will be presented. This discussion will include preclinical and clinical data for tazemetostat undifferentiated tumors with deficient expression of the mSWI/SNF subunits, such as INI1 and SMARCA4.

8:40 Targeting Histone Lysine Methylation in Cancer

Patrick Trojer, Ph.D., Vice President, Constellation Pharmaceuticals, Inc.

The development of small molecule KMT and KDM inhibitors constitutes an attractive approach to selectively alter histone methylation patterns and transcriptional programs, ultimately allowing for the suppression of aberrant gene expression in cancer cells. The discovery of KMT and KDM inhibitors, their application in various oncology contexts, as well as mechanistic consequences of target inhibition will be discussed.

9:10 Development of Lysine-Specific Demethylase Inhibitors for Oncological and Neurodegenerative Disease

Tamara Maes, Ph.D., Co-Founder, Vice President & CSO, Oryzon Genomics S.A.

Here we will discuss the advances in the development of ORY-1001, a potent selective inhibitor of LSD1, for the treatment of leukemia and other malignancies; and of ORY-2001, a dual inhibitor of LSD1 and MAO-B, for the treatment of neurodegenerative diseases. ORY-1001 is currently in a Phase I/IIa trial in recurrent or recalcitrant acute leukemia nearing completion. We have recently initiated a Phase I trial with ORY-2001 to assess the compounds’ tolerability, pharmacokinetics and pharmacodynamics in healthy young and elderly volunteers.

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


ADVANCES IN TARGETING ARGININE METHYLTRANSFERASE PRMT5

10:25 PRMT5 Inhibition as a Therapeutic Strategy for Solid and Heme Malignancies

Olena Barbash, Ph.D., Investigator, Oncology R&D, GlaxoSmithKline

This presentation will highlight new data by GSK on targeting PRMT5 as a therapeutic strategy for solid and hematological malignancies.

10:55 PRMT5 is an Oncogenic Driver and an Ideal Therapeutic Target for Solid and Hematologic Cancers

Robert A. Baiocchi, M.D., Ph.D., Associate Professor, Division of Hematology, Department of Internal Medicine, The Ohio State University

Recent work has identified the PRMT5 enzyme to be dysregulated and acting as an oncogenic driver in both solid and hematologic malignancies. PRMT5 overexpression exhibits these driver properties by methylating both histone and non-histone proteins promoting transcriptional silencing of regulatory genes, supporting cell signaling networks (BCR, PI3K), cell cycle (CYCLIND1), and survival (P53, NFkB) and growth pathways (MYC). Here we will summarize the biologic relevance of PRMT5 in malignant disease and our efforts in developing highly selective inhibitors.

11:25 Enjoy Lunch on Your Own



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

3:20 End of Conference



Day 1 | Day 2 | Download Brochure

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 PREMIER SPONSOR

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

Medical Dermatology Therapeutic R&D and Technical Innovation

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