2017 Archived Content

Targeting Histone Methyltransferases and Demethylases

Targeting the histone methylome as a therapeutic strategy continues to capture the interest of developers due to the genetic and expression abnormalities displayed in a variety of human cancers, as well as the chemically tractable nature of modifying enzymes. Over the past few years, developers have intensely pursued these targets, resulting in the rapid entry of histone methyltransferase (HMT) and histone demethylases (HDM) inhibitors into the clinical. Recently, interest in developing inhibitors against arginine methyltransferase enzymes, targeting of protein-protein interactions of enzyme complexes, and designing HMT and HDM inhibitors for combination cancer immunotherapy has provided new avenues for continued development.  

Cambridge Healthtech Institute’s 6th Annual Targeting Histone Methyltransferases and Demethylases conference will once again gather an interdisciplinary collection of leaders working to advance epigenetic drug discovery.

Final Agenda


• September 25 Symposium: Immunomodulatory Small Molecules

• September 25 Short Course: Covalent Fragments: Applications in Target-Based and Phenotypic Screens

• September 26-27 Conference: Targeting Histone Methyltransferases and Demethylases

• September 27-28 Conference: Next-Generation Histone Deacetylase Inhibitors

• September 27 Short Course: Impact of Convergence of Immunotherapy and Epigenetics on Drug Discovery

• September 28-29 Symposium: CNS and Neurodegenerative Targets

Tuesday, September 26

7:00 am Registration Open and Morning Coffee


8:00 Welcome Remarks

Kip Harry, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Dafydd Owen, Ph.D., Associate Research Fellow, Pfizer

8:10 KEYNOTE PRESENTATION: Discovery of Selective Inhibitors for Histone Methyltransferases

Jian_JinJian Jin, Ph.D., Professor, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai

Histone methyltransferases (HMTs) have received great attention as a new class of potential therapeutic targets. High-quality selective inhibitors of HMTs will permit biological and disease hypotheses concerning these enzymes to be tested with high confidence in cell-based and/or animal models. Our laboratory has made significant progress on discovering selective inhibitors of HMTs by pursuing three complementary structure-based inhibitor discovery approaches. Our recent discoveries of selective HMT inhibitors using these approaches will be presented.

8:40 Structure of the PRC2 Complex: Implications for Inhibitor Discovery

Karen_MaegleyKaren A. Maegley, Ph.D., Associate Research Fellow, Pfizer

Several inhibitors of PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. The crystal structures of the inhibitor-bound wild-type and Y641N PRC2 illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2 in inhibitor recognition and the potential development of mutation-mediated drug resistance. This work provides new insights for the design and development of next-generation PRC2 inhibitors.

9:10 Crosstalk Affects Activity of Histone Methyltransferases

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

Histone methyltransferases (HMTs) are involved in a broad range of biological processes. Their roles in regulation of gene expression have been extensively studied in relation to diseases including cancers. Here we will discuss the data indicating how the activities of some HMTs are affected by crosstalk between methylation and other histone posttranslational modifications.

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


10:25 An S-Adenosyl Methionine-Inspired Chemical Probe for SMYD2

Dafydd_OwenDafydd Owen, Ph.D., Associate Research Fellow, Pfizer

Research into Histone Methyltransferases (HMTs) has benefitted from the disclosure of high-quality chemical probes from the scientific community. Higher-quality tools, available with no restriction on use, enable the small molecule perturbation cell biology as we study the role and function of poorly understood targets in human disease. While chemical probes for HMTs have been identified binding in both the substrate and co-factor sites, molecules that predominantly compete with the co-factor S-Adenosyl Methionine (SAM) are in the minority. The talk will discuss why that may be and disclose an inhibitor of SMYD2 that was designed starting from SAM as the initial screening hit.

10:55 Development of Sinefungin Derivatives as Selective Protein Methyltransferases Inhibitors

Xiaochuan_CaiXiaochuan Cai, Ph.D., Research Scientist, Lou Lab, Chemical Biology Program, Memorial Sloan Kettering Cancer Center

Our recent progress highlights the development of sinefungin analogues as selective PMT inhibitors, guided by molecular rationale based on in silico simulation and X-ray crystallography. Here we concluded that even closely related PMTs can adopt distinct conformational states, though not necessarily for the apo-enzymes, and thus be selectively recognized by small molecule inhibitors.

11:25 Fragment-Based Discovery of WDR5-MLL1 Disruptors

Shaun_StaufferShaun 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.

11:55 Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson’s Remarks

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

1:55 Targeting the PRC2 Complex through a Novel Protein-Protein Interaction Inhibitor of EED

Chaohong_SunChaohong Sun, Ph.D., Senior Principal Research Scientist; Head, Fragment Based Drug Discovery, and Global Protein Sciences-Small Molecule, AbbVie

In this talk, we will present our discovery of A-395, a first-in-class antagonist of PRC2 protein-protein interactions (PPI). A-395 binds potently to EED, thereby allosterically inhibiting activity of PRC2 complex. It showed potent cellular activity and comparable in vivo activities to known EZH2 enzymatic inhibitors and furthermore, retained potent activity against cell lines resistant to the catalytic inhibitors, suggesting potential clinical benefits of this novel mechanism of targeting PRC2 complex.

2:25 Using Fragments to Find New Ways to Inhibit MethylTransferases

Gregg Siegal, Ph.D., Lecturer, Faculty of Science, Leiden Institute of Chemistry, Leiden University

The small size of fragments enables them to be used as probes of surface features that more lead-like compounds would miss. Careful design of biophysical binding assays can be used to efficiently sort out different binding sites and, where the target is an enzyme, the biological activity of hits can usually be determined rapidly. Using such an approach, we have discovered two novel small molecule binding sites on Dot1L and a new, non-nucleotide scaffold that targets the SAM co-factor site. The mode of action of these compounds was confirmed through X-ray crystallography studies. This is a perfectly general approach that can be used against an array of pharmaceutically relevant targets.

2:55 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced


4:05 FEATURED PRESENTATION: Metabolic Regulation of Histone Lysine Demethylases

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

Several classes of chromatin modifying enzymes utilize as cofactors metabolic intermediates such as S-adenosylmethione, acetyl-CoA, 2-oxoglutarate or NAD+, respectively, whose concentrations are subject to nutritional status and impact on global protein acetylation and methylation patterns. In this presentation our ongoing work will be presented that is related to metabolic regulation, inhibitor development and dependencies of histone demethylases in the context of chromatin modification.

4:35 Targeting JARID1/KDM5 Demethylases in Breast Cancer and Melanoma

Jian_CaoJian Cao, Ph.D., Associate Research Scientist, Department of Pathology, Yale School of Medicine

We have discovered novel mechanisms by which the KDM5 family histone demethylases regulate gene expression and promote tumorigenesis in breast cancer and melanoma. We also developed and evaluated inhibitors with selective specificity against the KDM5 family members, as well as pan-KDM5 inhibitors. These inhibitors could be further developed to target KDM5 histone demethylases in breast cancer and melanoma.

5:05 Interactive Breakout Discussion Groups

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below. Please click here for full details on all breakouts.

Chemistry of Histone Demethylase Inhibitors

Moderator: 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

  • Achieving potent and highly selective KDM inhibitors
  • Challenges in discovery of novel KDM chemical probes
  • New technologies supporting the discovery of KDM inhibitors

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?


6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)

7:10 Close of Day

Wednesday, September 27

7:30 am Registration Open and Morning Coffee


8:00 Chairperson’s Remarks

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

8:05 FEATURED PRESENTATION: Investigation of GSK2879552 in Combination with ATRA in AML

Helai Mohammad, Ph.D., Scientific Leader, Fellow, Cancer Epigenetics DPU, GlaxoSmithKline

GSK2879552, an inhibitor of lysine demethylase 1 (LSD1), can promote differentiation and inhibit the growth of human acute myeloid leukemia (AML) cells. Treatment of non APML-AML cell lines with the combination of GSK2879552 and ATRA results in enhanced growth inhibition and cytotoxic response. Supra-additive effects were observed upon evaluation of cell surface markers associated with myeloid differentiation and caspase activation, a hallmark of apoptotic cell death.

8:35 INCB059872, LSD1 Specific Inhibitor, as a Potential Therapeutic Agent for Advanced Malignances

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

LSD1 functions as an epigenetic eraser, and its overexpression is associated with many human cancers. We have previously reported that a LSD1 specific inhibitor, INCB059872, potently inhibits tumor cell growth in preclinical models of AML and SCLC. This presentation will focus on the exploration of the potential therapeutic utility of INCB059872 in additional cancer indication and in novel combination therapeutic strategies.

9:05 Selected Poster Presentation: LSD1 Modulation by Allosteric Ligands

Bremberg Ulf, Ph.D., CSO, Beactica AB

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:20 Development of Lysine-Specific Demethylase Inhibitors for Oncological and Neurodegenerative Disease

Tamara_MaesTamara 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/RG6016 has finalized in a Phase I/IIa trial in recurrent or recalcitrant acute leukemia and is currently in a Phase I trial for small cell lung cancer. A Phase I trial with ORY-2001 to assess the compounds’ tolerability, pharmacokinetics and pharmacodynamics in healthy young and elderly volunteers is nearing finalization and the compound is being moved forward in neurodegenerative diseases including Alzheimer's and multiple sclerosis.

10:50 Chemical Probes Targeting Histone Modification for Cancer Research and Therapy

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

11:20 Enjoy Lunch on Your Own

12:35 pm Plenary Keynote Program

(click here for details)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

2:45 Close of Conference