Epigenetic Inhibitor Discovery

A New Frontier in Drug Development

April 23-24, 2014 


Within the past few years, an expanding collection of epigenetic modulators - spanning multiple classes and disease implications - have been positioned as promising targets for therapeutic development. Since the approval of first-generation epigenetic therapies, an increasing amount of chemically tractable epigenetic targets, such as Histone Deacetylases (HDACs), Histone Methyltransferases (HMTs), Histone Demethylases (HDMs), and a distinct set of chromatin readers - the BET family bromodomains - have given rise to novel inhibitors that are now in preclinical and clinical development. However, obtaining potent, highly-selective and cell-active inhibitors requires skillful utilization of varied assays and screening methods, such as high-throughput screening (HTS), focused screening, knowledge/fragment-based approaches, and phenotypic assays to efficiently navigate lead discovery of epigenetic targets. Cambridge Healthtech Institute is proud to announce the inaugural Epigenetic Inhibitor Discovery conference, gathering a diverse cross-section of academic and industry leaders actively working on developing epigenetic inhibitors.

Great opportunity to share and discuss cutting-edge approaches/aspects in drug discovery.

Fabrizio G., Principal Scientist, AstraZeneca

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Wednesday, April 23 - Day 1 


7:00 am Registration and Morning Coffee



8:00 Chairperson’s Opening Remarks

Alison O'Mahony, Ph.D., Senior Director, Biology Research, BioSeek®, A Division of DiscoveRx Corp.

8:10 Discovery and Optimization of BET Bromodomain Inhibitors

Michael HewittMichael Hewitt, Ph.D., Principal Scientist, Medicinal Chemistry, Constellation Pharmaceuticals

The BET bromodomain class of chromatin reading domains have emerged as new and exciting epigenetic targets for the potential treatment of cancer and immunological disorders. Inhibition of these targets leads to profound effects in relevant models of disease. The discovery and optimization of potent and selective BET bromodomain inhibitors will be presented.

8:40 Targeting Epigenetic Readers for Cancer Therapy

hun QiJun Qi, Ph.D., Senior Research Scientist, Medical Oncology, Dana-Farber Cancer Institute

Epigenetic proteins are promising and intensely studied targets for therapeutic drug discovery in cancer. Among the chromatin modifying enzymes, so-called epigenetic “writers”, “reader” and “erasers”, chromatin binding modules or epigenetic “readers” are more difficult targets perhaps owing to perceptions regarding the difficulty of targeting protein-protein interactions. We have recently developed first-in-class, drug-like inhibitors of “bromodomain and extraterminal domain” epigenetic readers (BETs) for mechanistic study and therapeutic application in cancer and other diseases. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations.

9:10 Cracking the Histone Code: Development of Inhibitors of the Bromodomain-Histone Interaction

Stuart ConwayStuart Conway, Ph.D., Associate Professor, Chemistry, University of Oxford

I will describe the development of our published BET bromodomain inhibitors and our unpublished work on the development of potent CREBBP bromodomain inhibitors. This will include a discussion on the development of cutting-edge bromodomain ligands, as well as the SAR, structure-based design and cellular action of two classes of bromodomain inhibitors.

9:40 Coffee Break



10:05 Screening for Inhibitors of Bromodomain 4 … Have We Learned Something? … You BET!

Paul Bonin, Principal Scientist, Assay Development and Pharmacology, Primary Pharmacology Group, Pfizer, Inc.

Bromodomain (BRD) 4 is a member of a family of reader proteins (BET family) that recognize acetylated lysine residues on core histone tails of DNA. Binding of these reader proteins to their epigenetic marks orchestrates the way in which gene expression is regulated by chemical (epigenetic) instructions. Recent studies have suggested that BRD4 may play a role in the pathology of a number of diseases including cancer, inflammation and metabolic disorders. Accordingly, it has been postulated that inhibitors of BRD4 may prove to be useful therapeutic agents for these diseases. To identify inhibitors of BRD4, a fluorescence polarization (FP) assay was developed that utilized a version of the novel BET family chemical probe PFI-1 labeled with a Cy5 dye. Binding of this probe to BRD4 as well as other BET family members (BRD2, BRD3, BRDT) was characterized. In addition, the ability of the BRD4 FP assay to identify legitimate fragment library hits will be compared to the ability of other assay technologies including surface plasmon resonance (SPR), time resolved fluorescence resonance energy transfer (TR FRET) and AlphaScreen®. In this presentation, I will discuss the identification and characterization of a novel fluorescently-labeled BRD4 probe and learning’s from our experience using several different assay formats/technologies to screen a fragment library and for inhibitors of BRD4.

10:35 Targeting Bromodomains - The Validity of High-Throughput Virtual Screening in Epigenetic Drug Discovery

Stefan GuentherStefan Günther, Ph.D., Professor, Institute of Pharmaceutical Sciences, Pharmaceutical Bioinformatics, University of Freiburg

Bromodomains are acetyl-lysine epigenetic mark reader proteins. Small molecules inhibiting them have potential as anti-inflammatory, antiviral, and anticancer agents. We report the identification of novel scaffolds which potently inhibit specific bromodomains and exhibit antiproliferative activity against leukemia cell lines.


11:05 An NMR Pyramid for Epigenetic Drug Discovery

Gregg SiegalGregg Siegal, Ph.D., CEO, ZoBio

Fragment based drug discovery is a powerful means to develop small molecule modulators of challenging pharmaceutical targets. The challenge often lies in the limitations of the biophysical methods required to carry out a campaign, in particular with obtaining 3D structural information. ZoBio has developed a concept that we call the NMR Pyramid that is specifically designed to meet these challenges. The application of the NMR Pyramid for hit discovery, validation and structural biology to bromodomains and histone lysine methyl transferases will be illustrated.


11:35 Luncheon Presentation: Epigenetic Targets: Potential New Tools for Treating Fibrosis

Alison O'MahonyAlison O'Mahony, Ph.D., Senior Director, Biology Research, BioSeek®, A Division of DiscoveRx Corp.

The development of fibrosis marks the final stage of many lung and kidney diseases and despite the broad range of potential treatment targets, an effective clinical therapeutic does not exist. Part of the challenge for this indication may be due, at least in part, to the fact that the cellular events contributing to the fibrotic phenotype are part of the normal wound healing process and as such must be effective, regulated and redundant. To date both mono-therapies and combination therapies have failed to block the progression to fibrosis. This has prompted renewed efforts toward developing innovative screening approaches for evaluating new targets and biomarkers with the goal of discovering anti-fibrotic compounds with better clinical outcomes. To support therapeutic development in this area, we have expanded our BioMAP® in vitro assay platform to include Fibrosis model systems using primary human renal and lung epithelial cells co-cultured with fibroblasts and stimulated with both TGFβ and TNFα. We evaluated a range of fibrosis-related readouts as predictive biomarkers using both clinical drugs and tool compounds and also assessed the anti-fibrotic potential of compounds in the newly emerging epigenetic target space. Bromodomain inhibitors (BET family) are highly active in BioMAP® systems with phenotypic signatures reflecting anti-inflammatory effects, matrix-remodelling activities and reduced expression of fibrosis markers. By providing physiologically-relevant human cell data on disease biomarkers, primary versus secondary target effects, safety-related activities, dose responses and comparison of mono- versus combination agents, the BioMAP® platform can help guide the discovery and development of new therapeutic strategies for treating fibrosis.

12:05 pm Session Break



1:15 Chairperson’s Remarks

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

1:20 Histone Methyltransferase Inhibitors: Fast-Acting Molecules against Blood and Liver Stage Malaria Parasites

Matthew FuchterMatthew Fuchter, Ph.D., Senior Lecturer, Synthetic and Medicinal Chemistry, Department of Chemistry, Imperial College London

We have pursued natural product and synthetic histone lysine methyltransferase (HKMT) inhibitors as novel therapeutics for malaria. We have identified highly active compounds that produce: rapid, stage- unspecific and irreversible killing of blood stage P. falciparum parasites with comparable potency against resistant strains; rapid activity in vivo; and unprecedented activating activity toward liver stage hypnozoites of P. cynomolgi parasites. Taken together this positions the HKMTs as a highly exciting new target class for the development of novel anti-malarials.

1:50 Discovery and Characterization of a Jumonji Histone Demethylase Inhibitor with in vivo Activity

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

I will discuss the development of a cell-based assay used in HTS to identify epigenetic modulators of gene expression. Using the small molecule JIB-04 as an example, I will describe the characterization of the mechanism of action of active compounds and their activity in cells and in animal models of disease, particularly in cancer.


2:20 Selected Poster Presentation: Biochemical Characterization and Computational Analysis of Phenylglycine Inhibitors of Mutant IDH1

Eric T. Baldwin, Ph.D., Senior Scientist, CBC Biology NExT Program Support, Leidos Biomedical Research

2:35 Refreshment Break in the Exhibit Hall with Poster Viewing

3:20 Chemical Probes for Histone Demethylases

XiangWangXiang Wang, Ph.D., Assistant Professor, Chemistry and Biochemistry, University of Colorado at Boulder

Histone demethylases are the latest class of histone modifying enzymes that have profound impacts on a variety of cellular processes and disease processes. Specific chemical probes are not only important to assist the elucidation of their cellular functions, but also critical to evaluate them as “druggable” targets to treat diseases. We have made and will continue to make significant progress in developing novel probes for both applications. In this presentation, I will discuss knowledge-based design of selective chemical probes, novel functions of histone demethylases, and potential applications of histone demethylase inhibitors in disease-relavant context

3:50 Discovery of Histone Lysine Demethylase Inhibitors

Takayoshi SuzukiTakayoshi Suzuki, Ph.D., Professor, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

As there is increasing evidence that lysine demethylases (KDMs) are associated with various disease states, they have emerged as attractive targets for the development of new therapeutic drugs. We have identified several classes of KDM inhibitors. This presentation will discuss the design, synthesis, and evaluation of our most recent KDM inhibitors and their possibility as anticancer agents will be presented.

4:20 Session Break


» 4:30 Plenary Keynote Presentation: Drug Discovery for Challenging Targets

James WellsJames Wells, Ph.D., Professor, Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California San Francisco

I will present work from our lab for two classes of challenging targets: protein-protein interfaces and novel allosteric sites, both to activate and inhibit protein function. We use a site-directed fragment-based discovery method, called Tethering, coupled to HTS approaches that are well-suited to probing these challenging surfaces. These approaches have led to the discovery of potent and selective compounds and some with surprising properties that will be discussed.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 Close of Day

Thursday, April 24 - Day 2 



In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic 7: Screening  and Development of Novel BET Bromodomain Inhibitors

Moderator: Stefan Günther, Ph.D., Professor, Institute of Pharmaceutical Sciences, Pharmaceutical Bioinformatics, University of Freiburg

• What are the critical limitations for the BET-bromodomains as targets for new drugs?
• Which bromodomains, apart from the BET family come into question for new drug targets?
• Which diseases can be addressed by bromodomain inhibitors?
• Which methods have been successfully applied for the discovery of new bromodomain inhibitors?
• What is the academic role in the drug discovery process for novel epigenetic drugs?

Topic 8: Challenges in Targeting Histone Demethylases

Moderator: Helena Danielson, Ph.D., Professor, Biochemistry, Uppsala University; CSO, R&D, Beactica

• What is the optimal strategy for selective inhibition of histone demethylases?
• Are we any more or less likely to find hits for this target class over other enzyme or epigenetic target classes?
• How do we demonstrate target engagement of histone demethylases in vivo?
• What is the experience so far?

Topic 9: Considerations for Histone Methyltransferase Assay Development

Moderator: Karen Maegley, Ph.D., Associate Research Fellow, Integrative Biology and Biochemistry, Oncology, Pfizer, Inc.

• 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?



8:40 Chairperson’s Remarks

Matthew Fuchter, Ph.D., Senior Lecturer, Synthetic and Medicinal Chemistry, Department of Chemistry, Imperial College London


» 8:45 Featured Presentation: A Multifaceted Strategy for Discovering Chemical Probes of Histone Methyltransferases

Jian JinJian Jin, Ph.D., Associate Professor and Director, Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill

Histone methyltransferases (HMTs) have received great attention as a new class of potential therapeutic targets. However, very few chemical probes of HMTs have been created. To address this issue, our laboratory has pursued a multifaceted structure-based probe discovery strategy. Progress on discovering substrate-competitive probes of G9a and GLP, allosteric inhibitors of PRMT3, and cofactor-competitive probes of EZH2 and EZH1 will be presented.

9:15 Targeting the Recruitment of Histone Methyltransferase DOT1L

Zaneta NColeskaZaneta Nikolovska-Coleska, Ph.D., Assistant Professor, Pathology, Medical School, University of Michigan

MLL-fusion proteins use similar strategy for leukemic transformation through DOT1L recruitment. We have characterized the protein-protein interactions between DOT1L and MLL-fusion proteins, AF9/ENL, on biochemical, biophysical and functional level. The AF9/ENL binding site in human DOT1L was mapped and the interaction site was identified to a 10 amino-acid region. Functional studies show that the mapped AF9/ENL interacting site is essential for immortalization by MLL-AF9, indicating that DOT1L interaction with MLL-AF9 and its recruitment are required for transformation by MLL-AF9. These results strongly suggest that disruption of interaction between DOT1L and AF9/ENL is a promising therapeutic strategy with potentially fewer adverse effects than enzymatic inhibition of DOT1L for MLL-fusion protein-associated leukemia. Our studies have demonstrated for the first time, a novel approach for inhibiting the histone methyltransferase activity of DOT1L through blocking DOT1L recruitment by MLL-fusion proteins, AF9 and ENL. These results lay a foundation towards discovery of small-molecule inhibitors able to inhibit these PPI and thereby blocking the MLL fusion-mediated leukemogenesis.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Fragment-Based Discovery of KDM Inhibitors

Helena DanielsonHelena Danielson, Ph.D., Professor, Biochemistry, Uppsala University; CSO, R&D, Beactica

SPR is a relatively novel approach for fragment-based discovery of leads. Our creative experimental designs and data analysis procedures result in novel types of compounds for KDM targets. This presentation will demonstrate the use of SPR biosensor analysis for fragment-based discovery of inhibitors targeting two different types of KDMs. Procedures for screening and characterisation of the hits, and their subsequent evolution into leads will be presented. Attendees will gain an understanding of how to target KDMs, and how to implement SPR biosesnsor technology for fragment-based lead discovery.

11:00 Chemical Probes to Explore Epigenetic Pathways

Susanne MKnappSusanne Muller-Knapp, Ph.D., Epigenetic Project Manager, Structural Genomics Consortium (SGC), Oxford

Recently described epigenetic probe molecules have opened new areas for targeting this new class of proteins. We have established a chemical biology platform for the development of highly specific and potent chemical tool compounds that target histone lysine demethylases and bromodomains. Recently developed probe molecules and their impact on target validation will be presented.

11:30 Defining the Functional Consequences of Isoform- Specific Inhibition of the Class I HDACs Using a Chemical Genetics Approach

Ed HolsonEdward Holson, Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard

Utilizing a chemical toolkit of highly selective HDAC inhibitors we have taken an unbiased approach to defining the biological outcome of small molecule inhibition of the individual HDAC isoforms. We have characterized and profiled a number of known and novel HDAC inhibitors and examined the effects on histone and non-histone acetylation, and gene expression and functional responses in a number of cell types. This work represents the cutting edge of developing and understanding selective inhibitors of individual HDAC isoforms and the application of these inhibitors in metabolic and neurological diseases. This work reveal new insights on the role of individual HDACs in gene expression and reveal new substrates for the individual HDAC isoforms which have not been described. The focused application of highly selective inhibitors in non-oncology indications will be discussed.

12:00 pm Close of Track

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