2015 Archived Content


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:

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.

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.

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 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.

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

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.

Considerations for Histone Methyltransferase Assay Development

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

  • What are the options (direct enzymatic/binding assays vs. indirect assays)?
  • What are the limitations and opportunities of each approach?
  • How do different substrates or changes in nucleosome structure alter the enzyme active site?

The Challenge of Enabling Structural Biology for HKMTs

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

  • Dissussion Questions to be Announced


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

Alan Graves, 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 Inhibition of the MLL-Menin Interaction with Small Molecules for Epigenetic Therapy in Cancer 

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

The protein-protein interaction between menin and MLL or MLL fusion proteins is implicated in development of acute leukemias and solid tumors. Using structure-based design combined with extensive medicinal chemistry, we developed very potent small molecule inhibitors of the menin-MLL interaction with optimized drug-like properties, including pharmacokinetic profile, making them suitable for in vivo studies in mice. These compounds demonstrate strong effect and specific mechanism of action in MLL leukemia cells. More importantly, the menin-MLL inhibitors we developed block progression of acute leukemia in vivo in mice models of MLL leukemia through on target mechanism of action, validating their therapeutic potential. Broader applications of these compounds in solid cancer models will be discussed as well. Our work provides an example of successful targeting of protein-protein interactions to block histone methyltransferase activity of MLL for therapeutic applications in cancer.

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 with different substrates 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 Copy Number Heterogeneity: Roles for Chromatin and Stress

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

Acquired somatic copy number alterations are a hallmark of cancer; however, the mechanistic basis for their occurrence remains unclear. We have recently identified the histone tri-demethylase KDM4A as the first enzyme capable of promoting site-specific copy number changes. KDM4A over-expression promotes localized copy gain without global chromosome instability. Tumors with increased KDM4A levels are enriched in copy gains for cytobands observed in cell culture models. We further demonstrate that these events are the result of re-replication. KDM4A alters heterochromatin and increases the amount of replication machinery at target loci. These copy gains occur during S phase and are removed as cells are exiting S phase. The cytoband gains are affiliated with drug resistant tumors; therefore, we asked whether targeting the copy gains through chemical inhibition of KDM4A was possible and whether a chemical screen could demonstrate that an active process is associated with elimination of copy gained regions. Our most recent data demonstrates the druggability of these processes. In fact, we have now identified small molecules that impact KDM4A and copy gain as well as the ability to remove gains during cell cycle progression. Lastly, a screen for environmental and chemical agents has uncovered input signals that are responsible for generating site-specific gains through altering the chromatin environment. Taken together, we have identified genetic, epigenetic and environmental factors promoting copy number heterogeneity in tumors and established that these events are targetable through inhibition of chromatin regulators.

2:50 Nitric Oxide is an Epigenetic Regulator of Gene Expression via Inhibition of JmjC-domain Containing Histone Demethylases

Douglas Thomas, Ph.D., Associate Professor, Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago

Nitric oxide (NO, nitrogen monoxide) is an endogenously produced free radical signaling molecule with numerous purported roles in health and disease. Our recent findings provide a direct mechanistic link between cellularly-derived •NO and significant changes in histone posttranslational modifications (PTMs) by demonstrating its ability to inhibit the catalytic activity of JmjC-domain containing histone demethylases. These results reveal a novel signaling mechanims of NO and demonstrate that a significant proportion of NO-driven transcriptional responses arise from changes in histone PTMs.

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

John McGrath, Ph.D., Senior Scientist, 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

Scott Ribich, Ph.D., Associate 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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Suggested Event Package:

September 21 Symposium: Next Generation Histone Deacetylase Inhibitors

September 22-23 Conference: Targeting Epigenetic Readers and Chromatin Remodelers

September 23-24 Conference: Targeting Histone Methyltransferases and Demethylases