Targeting the histone methylome as a therapeutic strategy has quickly captured the interest of developers worldwide, due to the genetic and expression abnormalities of histone methyltransferases and demethylases displayed in a variety of human cancers, as well as the chemically tractable nature of these modifying enzymes. Adding to the more established series of histone methyltransferase targets, histone demethylases of both JmjC and CoREST domains have also advanced into clinical development and are now showing favorable clinical outcomes. Notably, increased interest in developing inhibitors against arginine methyltranslferase enzymes has substantially deepened the possibilities of regulating chromatin environments via histone methylation, and thereby expanding this already robust target space.

Cambridge Healthtech Institute will once again convene leaders in epigenetic drug development to further our understanding of the role aberrant histone methylation plays in disease, to evaluate lead and clinical compounds by developers, and to introduce novel chemical matter for further development.

Final Agenda

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Wednesday, September 23

11:30 am Registration

12:55 pm Plenary Keynote Program 

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


3:25 Chairperson’s Opening Remarks

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

3:35 FEATURED PRESENTATION: Targeting the Histone Demethylome

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

Chromatin modifications such as histone lysine methylation and demethylation are effector systems that are considered components of the “epigenetic machinery”. Recent data suggest that histone demethylases are chemically tractable targets, and furthermore, that demethylase selective small molecules may be useful tools to dissect chromatin driven biological processes. Data will be presented to illustrate the usefulness of these tool compounds to understand demethylase involvement in oncology and stem cell biology.

4:05 JARID1/KDM5 Demethylases as Cancer Targets

Qin Yan, Ph.D., Associate Professor, Department of Pathology, Yale School of Medicine

Epigenetic aberrations often lead to cancer and other human diseases. My laboratory focuses on the roles and regulatory mechanisms of the JARID1/KDM5 histone demethylases. The JARID1A/B demethylases play critical roles in tumor formation, metastasis and drug resistance, and therefore are novel targets for cancer treatment. We have identified novel mechanisms by which the JARID1 enzymes regulate gene expression and promote tumorigenesis. Our drug development platform has identified not only pan-JARID1 inhibitors, but also inhibitors with selective specificity against the JARID1 family members. The implications of these results in cancer treatment will be discussed.

4:35 The Interaction of Marketed Drugs on a Panel of Epigenetic Targets

Jacques C. Migeon, Ph.D., Principal Scientist, Eurofins Pharma Discovery Services

In an effort to better understand the interaction of marketed pharmaceuticals with the growing number of epigenetics targets available, we ran 1000 drugs on a panel of 16 epigenetic targets. The result of this screening will be presented and discussed.

4:50 Sponsored Presentation (Opportunity Available)

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

5:40 Inhibition of LSD1 as a Therapeutic Strategy for the Treatment of AML and SCLC

Ryan Kruger, Ph.D., Director, Discovery Biology, GlaxoSmithKline

Lysine specific demethylase 1 (LSD1) is a H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. Pre-clinical data demonstrate that pharmacological inhibition of LSD1 causes differentiation of AML cells in vitro and in vivo. In SCLC cell line and primary sample xenograft studies LSD1 inhibition resulted in potent tumor growth inhibition. The current study describes the anti-tumor effects of GSK2879552, a novel, potent, selective, irreversible LSD1 inhibitor currently in clinical development.

6:10 Development of Histone Demethylase Inhibitors for Oncological and Neurodegenerative Disease

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

LSD1 inhibitors were shown to selectively abrogate the clonogenic potential of acute myeloid leukemia cells with MLL translocations, sparing the repopulating potential of normal hematopoietic stem cells. ORY-1001 is a potent, selective LSD1 inhibitor, with excellent pharmacological characteristics. ORY-1001 reduces leukemic stem cell potential, potently inhibits colony formation, overcomes the differentiation block in AML cell lines, and induces apoptosis/inhibits proliferation at sub-nanomolar concentrations in selected AML cell lines. ORY-1001 is currently in Phase I studies in UK and Spain and has been partnered with Roche. ORY-2001 is a dual LSD1/MAO-B inhibitor with near equipotent activity in both targets but selective over MAO-A and other FAD dependent aminooxidases. The compound effectively protects mice from MPTP insult, demonstrating its brain MAOBi capacity, and restores the memory loss of SAMP-8 mice, a non transgenic model for accelerated aging and Alzheimer disease. The mechanisms by which ORY-2001 acts on the mouse hippocampus will be discussed.

6:40 Close of Day

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Thursday, September 24

7:30 am Registration

8:00 Interactive Breakfast Breakout Discussion Groups


8:45 Chairperson’s Remarks

Karen Maegley, Ph.D., Associate Research Fellow, Biochemistry and Primary Screening, Pfizer Oncology

8:55 Structural Chemistry of Protein Methyltransferases

Matthieu Schapira, Ph.D., Principal Investigator, Computational Chemistry, Structural Genomics Consortium; Associate Professor, Department of Pharmacology & Toxicology, University of Toronto

As the number of chemical inhibitors and protein structures grows, the structural chemistry of protein methyltransferases is gaining in clarity. The druggability, structural diversity, and conformational dynamics of lysine and arginine methyltransferases, as well as chemical features of existing ligands will be reviewed.

9:25 Discovery of Chemical Probes for Histone Methyltransferases

Anqi Ma, Ph.D., Senior Research Scientist, Jian Jin Laboratory, Medicinal Chemistry, Chemical Biology & Drug Discovery, Icahn School of Medicine at Mount Sinai

Histone methyltransferases (HMTs), as a class of epigenetic writers, have received great attention due to potential therapeutic applications. However, only a limited number of chemical probes of HMTs have been discovered. To address this issue, our laboratory has been pursuing a multifaceted structure-based probe discovery strategy. Progress on discovering selective, substrate-competitive inhibitors of SETD8, a PRMT3 chemical probe which occupies a novel allosteric binding site, and a cofactor-competitive EZH2 and EZH1 chemical probe which effectively blocks proliferation of MLL-AF9 transformed murine progenitors will be presented.

9:55 Discovery of a Novel Smyd3 Inhibitor That Bridges the SAM-and MEKK2-Binding Pockets

Glenn Van Aller, Ph.D., Investigator, Cancer Epigenetics, GlaxoSmithKline

SET and MYND Domain Containing Protein 3 (Smyd3) is a lysine methyltransferase implicated in cancer progression and has been shown to catalyze methylation of Histone H4 at K5 and MEKK2 at K260. MEKK2 methylation has recently been described as important for regulation of the MEK/ERK pathway in RAS-driven tumors. The current study describes the identification and characterization of a novel, potent, SAM-competitive inhibitor of Smyd3 (Ki = 14 nM). GSK2807 has 24-fold selectivity against the closely related enzyme Smyd2. A high resolution crystal structure demonstrates that GSK2807 bridges the gap between the SAM binding pocket and the substrate lysine tunnel of Smyd3. Studies to investigate the mechanism of inhibition indicate that GSK2807 forms a ternary complex with Smyd3 and MEKK2. Molecular modeling studies support alternate conformations of the substrate lysine that suggest a structural mechanism for processive methylation events culminating in a tri-methylated state. Taken together these data indicate that Smyd3 catalyzed methylation of MEKK2 provides a novel opportunity to design modulators of RAS-driven tumor pathways.

10:25 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Winner Announced

11:10 Development of Potent Inhibitors of Menin-MLL Interaction with Strong Efficacy in Animal Models of Leukemia

Jolanta Grembecka, Ph.D., Assistant Professor, Department of Pathology, University of Michigan

Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients.

11:40 Mechanistic Characterization of PRMT5 Enzyme Complexes

Karen Maegley, Ph.D., Associate Research Fellow, Biochemistry and Primary Screening, Pfizer Oncology

PRMT5 methylates arginine residues on protein substrates. Many different PRMT5 complexes have been described and different complexes are suggested to have different substrate preferences. We have enzymatically characterized PRMT5 complexes and will compare and contrast mechanism of action and inhibition and suggest a potential regulation mechanism.

12:10 pm Is it Real, Or is it Virtual? Using the Domainex Technology Platform to Identify Novel Inhibitors of Lysine Methyltransferases

Trevor Perrior, Ph.D., Director, Research, Domainex Limited

Using its Combinatorial Domain Hunting and LeadBuilder platform technologies, Domainex has cloned a number of PKMT SET domains, and has identified novel classes of drug-like inhibitors. This powerful combination of virtual and library screening, as well as fragment-based drug design, is applicable to a wide-range of enzyme and protein-protein interaction targets nominated by Domainex or its collaborators.

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


2:15 Chairperson’s Remarks

Qin Yan, Ph.D., Associate Professor, Department of Pathology, Yale School of Medicine

2:20 Chromatin Modulators Provide a New Insight into Cancer Genomes

Johnathan R. Whetstine, Ph.D., Tepper Family MGH Research Scholar, Associate Professor of Medicine, Harvard Medical School and Massachusetts General Hospital Cancer Center

To date, enzymes that are capable of promoting site-specific copy number changes have yet to be identified. We have recently been able to demonstrate that H3K9/36me3 lysine demethylase KDM4A overexpression leads to localized copy gains without global chromosome instability. The copy gain occurs within a single cell cycle, requires S-phase and is not stable but regenerated each cell division. The regions with increased copy number are re-replicated and have increased KDM4A, MCM and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, while H3K9/K36 methylation interference promotes gain. Furthermore, analysis of tumors with KMD4A amplification supported these observations. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. These data begin to establish how copy number changes could originate during tumorigenesis and demonstrate that transient overexpression of chromatin modulators could promote copy change.

2:50 Critical Roles of Non-Histone Protein Methylation in Human Tumorigenesis

Ryuji Hamamoto, Ph.D., Associate Professor, Hematology & Oncology, The University of Chicago

A large body of evidence has indicated that dysregulation of histone methyltransferases and demethylases is involved in development and progression of human cancer. Importantly, beyond histones, the biological and physiological significance of non-histone methylation such as p53 and RB1 in human tumorigenesis has recently begun to be addressed. I will present the importance of non-histone protein methylation as biological regulator and its involvement in human cancer.

3:20 Session Break


3:30 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 Protein Arginine Methyltransferase 5 (PRMT5) enzyme to be dysregulated and act 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 of this oncogenic driver.

4:00 EZH2 Inhibitors and Their Application in Cancer

Patrick Trojer, Ph.D., Executive Director, Head, Biology, Constellation Pharmaceuticals

Constellation has identified potent, selective small molecule inhibitors of the histone H3 lysine 27 (H3K27)-specific methyltransferase Enhancer of Zeste Homolog 2 (EZH2). These compounds cause selective cell killing of Non Hodgkin Lymphoma cell lines and regression in subcutaneous NHL models in vivo. The impact on tumor growth is correlated with global reduction of H3K27me3 levels and the induction of EZH2 target gene expression. We have identified Multiple Myeloma as an additional potential application for EZH2 inhibitors.

4:30 FEATURED PRESENTATION: Discovery of EPZ015666: A First-in-Class PRMT5 Inhibitor with Potent in vitro and in vivo Activity

Jesse Smith, Ph.D., Executive Director, Biological Sciences, Epizyme

We describe the identification and characterization of EPZ015666 (GSK3235025), a potent, selective and orally available inhibitor of Protein Arginine Methyltransferase-5 (PRMT5). This novel inhibitor is SAM-uncompetitive, peptide-competitive and interacts with the PRMT5:MEP50 complex through a unique inhibition mode. Treatment with EPZ015666 on Mantle Cell Lymphoma (MCL) cells leads to inhibition of PRMT5 mediated methylation and cell killing.

5:00 Close of Conference

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Molecular Sensing 

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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:

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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