3rd Annual

Epigenetic Inhibitor Discovery

Targeting Histone Methyltransferases, Demethylases and Bromodomains

April 19-20, 2016

Epigenetic Inhibitor Discovery icon  

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 and JmjC-domain containing demethylases.

Cambridge Healthtech Institute will once again convene leaders in Epigenetic Inhibitor Discovery to bring forth novel and emerging strategies for inhibition, new bioactive tools and inhibitors, as well as strategies for lead optimization to obtain clinically relevant small molecules.

Final Agenda

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Tuesday, April 19

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

8:10 New Synthetic Routes to Triazolo-Benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition

Alessio Ciulli, Ph.D., Associate Professor & Principal Investigator, Chemical & Structural Biology, College of Life Sciences, University of Dundee

We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach.

8:40 FEATURED PRESENTATION: The Design and Development of Bromodomain Ligands

Stuart_ConwayStuart Conway, Ph.D., Professor, Department of Chemistry, University of Oxford

Bromodomains are protein modules that bind to N-ε-acetyl-L-lysine (acetyl lysine) and facilitate the assembly of multiprotein scaffolds by mediating protein–protein interactions. It is only comparatively recently that bromodomains have been viewed as therapeutically important targets, but subsequent progress in the development of drug-like bromodomain ligands has been rapid. This presentation will discuss advances in the development of BET bromodomain ligands and progress in the identification of non-BET bromodomain ligands.

PerkinElmer NEW 20099:10 Presentation to be Announced

9:40 Coffee Break

10:05 In silico Design of Dual PI-3 Kinase/BET Bromodomain Inhibitors; Structural Details for Binding BD1

Donald_DurdenDonald Durden, M.D., Ph.D., Professor, Vice Chair, Pediatrics, University of California, San Diego School of Medicine; CEO and President, SignalRx Pharmaceuticals

We will present in silico drug discovery of a lead compound which inhibits PI-3 kinase isoforms and BRD4. Specificity and potency are to be presented as well as biological data on the inhibition of tumor growth, metastasis, M1-M2 transition and the activation of the immune checkpoint response to activate immunity.

10:35 Design and Development of Novel BET Bromodomain Inhibitors

Eric_CampeauEric Campeau, Ph.D., PMP, Director of Biology, Zenith Epigenetics

Characterization of ZEN-3694, a novel pan-BET bromodomain inhibitor, and Zenith Epigenetics clinical candidate will be presented, including preclinical activity in relevant models. In addition, examples of next generation BET inhibitors, including compounds that are selective for either the BD1 or BD2 bromodomains of the BET proteins, and irreversible inhibitors of the BET proteins, will be discussed.

11:05 Development of Methyl Isoxazoleazepines as Inhibitors of BET

Michael_HewittMichael Hewitt, Ph.D., Director, CMC Project Management, Constellation Pharmaceuticals

In this presentation we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.

11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

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 Novel Dual Inhibitors of LSD1-HDAC for Treatment of Multiple Myeloma and Other Cancers

Dhanalakshmi Sivanandhan, Ph.D., Principal Scientist & Assistant Director, Jubilant Biosys

We have developed a set of molecules having dual activity on LSD1 and HDAC. Multiple compounds with dual activity show an in vitro potency of <0.05 µM against LSD1 with more than 1000 fold selectivity against MAOs. On HDAC, these dual inhibitors showed different isoform selectivity and molecules with LSD1/HDAC1, LSD1/HDAC6/8 and LSD1/pan HDAC activities have been identified. JBI-097, one of the dual molecules with LSD1/HDAC/6/8 selectivity showed an IC50 of µM on LSD1 and an IC50 of 0.04 and µM on HDAC6 and HDAC8, respectively with about 100 fold selectivity over other HDAC isoforms.

1:50 Small Molecule Modulators of Gene Expression for Use in Multiple Diseases

Patrick_WosterPatrick M. Woster, Ph.D., Endowed Chair, Drug Discovery; Professor, Pharmaceutical and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina

We have identified multiple series of small molecules and peptides that act as potent and selective LSD1 inhibitors. Because of their relatively low toxicity, we have explored the use of these molecules in diseases other than cancer, where cytotoxicity is not a desirable endpoint. In this presentation, we will describe the optimization of this new series of LSD1 inhibitors, and present evidence that LSD1 inhibitor-mediated correction of aberrant gene silencing can have therapeutic potential in a variety of disease states.

2:20 Discovery of Histone Lysine Demethylase Inhibitors with Anticancer Activity 

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

Recent studies have revealed that histone lysine demethylases (KDMs) are involved in transcriptional activation or silencing and associated with several disease states such as cancer. Since 2004, two classes of KDMs have been identified. One class includes lysine-specific demethylase 1 (LSD1, also known as KDM1A) and LSD2 (also known as KDM1B), which are flavin-dependent amine oxidase domain-containing enzymes. The other class comprises the recently discovered Jumonji domain-containing protein (JMJD) histone demethylases, which are Fe(II) and a-ketoglutarate-dependent enzymes. To date, we have identified several classes of KDM inhibitors including LSD1 inhibitors and JMJD inhibitors, and the feasibility of using KDM inhibitors as anticancer agents has been suggested. In this meeting, the design, synthesis, and evaluation of our most recent KDM inhibitors and their possibility as anticancer agents will be presented.

2:50 Targeting Histone Demethylases 

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

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


A New Model for Academic Translational Research

Peter SchultzPeter G. Schultz, Ph.D., Professor, Department of Chemistry, The Scripps Research Institute and Director, California Institute for Biomedical Research

Our research program combines the tools and principles of chemistry with the molecules and processes of living cells to synthesize new molecules and molecular assemblies with novel physical, chemical and biological functions. By studying the structure and function of the resulting molecules, new insights can be gained into the mechanisms of complex biological and chemical systems.

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

6:30 Close of Day

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Wednesday, April 20

7:30 am Continental Breakfast Breakout Discussions

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. Check our website in February to see the full listing of breakout topics and moderators.


8:30 Chairperson’s Remarks

Matthew Fuchter, Ph.D., Reader, Chemistry, Department of Chemistry, Imperial College London

8:35 FEATURED PRESENTATION: Profiling the ‘Methylome’ Targets of the Histone Lysine Methyltransferases: DOT1L

Matthew Fuchter, Ph.D., Reader, Chemistry, Department of Chemistry, Imperial College London

Indeed to date, no suitable technologies exist for defining the specific contribution of a given HKMT to the protein ‘methylome’. In currently unpublished work, we have gained proof-of-concept data towards the development a unique proteomic technology, via a traceable HKMT-cofactor system, that will allow cellular methylome profiling. We have initially applied our approach to DOT1L and in this talk I will present the underlying science of the method, the technological validation obtained so far, and the early insight we have gained on DOT1L biochemistry/biology.

9:05 Identification of a Novel Potent Selective SMYD3 Inhibitor with Oral Bioavailability

Lorna_MitchellLorna Mitchell, Ph.D., Associate Director, Medicinal Chemistry, Epizyme

SMYD3 (Set and Mynd Domain containing 3) is a lysine methyltransferase overexpressed in several cancer types including breast, prostrate, pancreatic, and lung, and this overexpression is associated with poor clinical prognosis. Genetic knockdown of SMYD3 by shRNA has been shown to decrease proliferation in a range of cancer cell lines suggesting that inhibition of SMYD3 may have therapeutic utility. In this presentation we describe the discovery and optimization of a novel series of oxindole sulfonamides and sulfamides with SMYD3 inhibitory activity. One of these compounds, EPZ030456, has a SMYD3 biochemical IC50 of 4 nM and is active in cells with an IC50 of 48 nM in a trimethyl MAP3K2 (MEKK2) in-cell western (ICW) assay. The crystal structure of this compound was solved with SMYD3 and the nucleotide substrate, S-adenosylmethionine and shows the oxindole portion of the molecule extends into the SMYD3 lysine binding channel. EPZ030456 shows less than 30% inhibition at a 10 uM screening concentration against 17 histone methyltransferase targets tested, including SMYD2. Further optimization within the series resulted in EPZ031686 which has similar potency to EPZ030456 with a biochemical IC50 of 3 nM and an ICW IC50 of 36 nM and in addition exhibits good bioavailability following oral dosing in mice. Hence, EPZ031686 is a suitable tool to study the role of SMYD3 in cancer and other therapeutic areas, using both in vitro and in vivo models.

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

10:30 Discovery of A-893, a New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Ramzi Sweis, Ph.D., Research Investigator, Discovery Chemistry, AbbVie, Inc.

A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

11:00 A Rational Approach for the Discovery of Inhibitors of NSD2 for the Treatment of Cancer

Christian_MontalbettiChristian A. G. N. Montalbetti, Ph.D., Head, Chemistry, Inventiva

We screened 240,000 compounds coming from our proprietary library. This strategy allowed us to identify about 200 compounds. To focus on the most interesting ones, orthogonal counterscreens based on [3]H SAM incorporation and biophysical binding are being completed. To our knowledge, no potent and selective NSD2 inhibitor has been identified to date despite several screening effort performed by other groups. Our library has already produced new chemical starting points for other KMTs, and we believe that our hits could be promising starting points to generate NSD2 inhibitors.

11:30 Chemical Tools to Modulate Gene Expression by Targeting DNA Methylation

Paola_ArimondoPaola B. Arimondo, Ph.D., Director, Research, ETaC - Epigenetic Targeting of Cancer, CNRS

A challenge to develop new anticancer strategies consists in designing chemical molecules able to modulate gene expression. To this aim we have designed inhibitors of DNA methyltransferases to reactive tumor suppressor genes. In order to identify novel inhibitors of DNA methylation, we applied three chemical strategies: High-Throughput Screening of chemical libraries, rational drug design based on molecular modeling and the pharmacomodulation of known inhibitors. The discovery and the biological activity of the compounds will be illustrated as the study of their mechanism of action.

12:00 pm Close of Track

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