Targeting Epigenetic Readers Header

About This Conference:

Epigenetic mechanisms work in concert to control transcriptional activity by altering the chromatin landscape of cells. Until recently, enzymatic modulators of writer and eraser classes have been the main focus of therapeutic development. Operating at the interface of translating histone marks, reader domains that recognize the histone code written in acetyl and methyl marks have now emerged as viable targets for therapeutic development. In particular, the BET bromodomain family of readers has gained significant attention for the treatment of human cancers, with several inhibitors developed and clinical-stage programs now underway. Adding to the collection of the already robust targets in reader, writer and eraser classes, strategies are now emerging to regulate gene activity by targeting components of remodelers such as the mammalian SWI/SNF chromatin remodeling complex - which displays functional mutations in several human cancers. In total, chromatin-associated proteins and readers represent significant opportunities for therapeutic intervention far beyond previously imagined.

Cambridge Healthtech Institute's Second Annual Targeting Epigenetic Readers and Chromatin Remodelers meeting will unite academic and industry researchers for the development of chemical probes, and clinical-stage inhibitors to further our understanding of the therapeutic opportunities associated with targeting reader domains and chromatin remodelers.

Wednesday, October 8

7:00 am Registration and Morning Coffee


8:05 Chairperson’s Opening Remarks

Ming-Ming Zhou, Ph.D., Harold and Golden Lamport Professor and Chairman, Department of Structural & Chemical Biology; Co-Director, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai

8:15 FEATURED PRESENTATION: Targeting Gene Expression: Selective vs. Promiscuous Bromodomain Inhibition

PanagisFilippakopoulosPanagis Filippakopoulos, Ph.D., Principal Investigator, Bromodomains, Structural Genomics Consortium & Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford

I will present our efforts to identify novel inhibitors of BRDs that are site selective (in the case of BET bromodomains) as well as our efforts to destroy selectivity while retaining affinity outside the BET family (i.e., promiscuous inhibitors). I will be covering the development and characterization of these tool compounds as well as their properties targeting gene expression in diverse cellular systems, seeking to validate BRD function.

9:00 Selective Modulation of Bromodomains in Gene Activation

Ming-Ming Zhou, Ph.D., Harold and Golden Lamport Professor and Chairman, Department of Structural & Chemical Biology; Co-Director, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai

The acetyl-lysine binding bromodomain proteins function to safeguard ordered gene transcription in chromatin, and are rapidly emerging as a new class of promising drug targets for a wide array of human disease. In this talk, I will present my group’s latest study of structural mechanism and function of bromodomain proteins in gene transcriptional activation using their newly designed, highly selective bromodomain inhibitors. I will discuss the functional implications of their new findings of basic principles that govern the molecular interactions and regulation in gene expression, and a new strategy for developing targeted epigenetic therapy for cancer and chronic inflammation.

9:30 Development and Utilities of BET Bromodomain Inhibitors with High CNS Exposure

Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor & Associate Dean, Therapeutic Innovation, Miller School of Medicine, University of Miami

Published bromodomain inhibitors show insufficient in vivo CNS exposure due to a variety off issues. In collaboration with Epigenetix Inc. we therefore developed novel small molecules, such as EP11313, with characteristics of CNS active drugs. These compounds have to date primarily been tested in various models of glioblastoma. However, they have also been useful in demonstrating a role for BET bromodomain proteins as novel epigenetic regulators of cocaine-induced behavioral plasticity.

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Discovery of Selective BRD4 Bromodomain Inhibitors by Fragment-Based High-Throughput Docking

Dimitrios Spiliotopoulos, Ph.D., Senior Research Scientist, Biochemistry, University of Zurich

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. The bromodomain containing protein BRD4 has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that selectively bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom). Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 10 million molecules, were tested in vitro.

11:15 Development and Application of BET and CREBBP Bromodomain Ligands

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

I will present our work on the development of small molecule ligands for the BET bromodomain. I will describe our understanding of the SAR for BET bromodomain binding and our work to optimize the structure of our ligands both for potency and metabolic stability for use in vivo. I will also present our work on the development of a novel class of CREBBP ligands and describe what these compounds have taught us about the requirements for CREBBP bromodomain binding.

11:45 A Novel Chemical Probe for Family VIII Bromodomains

Dafydd Owen, Ph.D., Associate Research Fellow, Medicinal Chemistry, Biotherapeutics Worldwide R&D, Pfizer

Mammalian SWI/SNF complexes play a key role in cell differentiation and proliferation, and represent an essential component of the embryonic stem cell. BRG1 (SMARCA4) and BRM (SMARCA2) are the central ATPase components of the multi-component complexes. BRG1 and BRM are multi-domain proteins that contain a number of DNA and protein interaction modules. These include C-terminal bromodomains. Through collaboration with the Structural Genomics Consortium we have identified a chemical probe that interacts with just three of the Family VIII bromodomains - BRG1, BRM and PB1(5). The discovery, binding mode and phenotype derived from the use of PFI-3 will be discussed.

Late-Breaking Research: Selected Poster Presentations*

12:15 Selected Poster I: Targeting the Acetyl-Lysine Binding Site of BRD4 with Dual BET-Kinase Inhibitors*

Nicholas Lawrence, Ph.D., Professor, Drug Discovery, H Lee Moffitt Cancer Center & Research Institute

Bromodomain (BRD)-containing proteins are essential for the recognition of acetylated lysine residues of histones during transcriptional activation.The BRD-containing proteins have emerged as promising drug targets for a number of diseases that are characterized by changes in the epigenetic cell signature. Recent reports have shown that targeting BRD4 with small molecules may represent a new way to treat prostate and breast cancer, acute myeloid leukemia and melanoma. We have found that 14 type 1 and 2 kinase inhibitors are also inhibitors of BETs. These were identified by robotic co-crystallization screening of kinase inhibitor libraries against BRD4. In each case the co-crystal structure unambiguously revealed the inhibitor bound to the acetyl lysine site of BRD4-1. The identified BRD4 ligands were subjected to differential scanning fluorimetry (DSF) and AlphaScreen assay to assess their binding and inhibitory potentials against BRD4. As shown previously for other BRD-inhibitor complexes, the melting temperatures of BRD4-kinase inhibitor complexes were logarithmically proportional to their IC50 values. We now report the design, synthesis and evaluation of next-generation BET-selective and dual-activity BET-kinase inhibitors, based on the initial co-crystallization screening hits. Structure activity relationships were developed using both DSF and co-crystallization with BRD4 to assess binding potential and binding modes. We report initial evaluation of the anticancer potential of compounds possessing dual potent BRD4 and kinase inhibitory properties.

12:30 Selected Poster II: Development of a Novel Potent Dual TRIM24/BRPF1 Bromodomain Inhibitor*

Wylie Palmer, Ph.D., Institute Research Scientist, MD Anderson Cancer Center

Bromodomains are an important class of chromatin remodeling proteins that recognize acetylated lysine residues on histone tails. As epigenetic targets they regulate gene transcription and offer a new way to target inflammatory and oncology diseases. The BET family of bromodomains has emerged as an important and druggable example of this class of proteins with the successful entry small-molecule inhibitors into the clinic. Other families of bromodomains are only starting to be explored. The Tripartite Motif-containing 24 protein (TRIM24) belongs to the TRIM/RBCC family of proteins is a multi-domain containing protein, with a dual PHD-bromo motif that recognizes the dual histone marks of unmodified H3K4 and acetylated-H3K23 within the same histone tail. TRIM24 is a potent co-activator of ER-alpha and overexpressed in many cancers. Increased expression of TRIM24 has been linked to poor survival rates in breast cancer patients. We sought to develop a TRIM24 bromodomain inhibitor tool compound in order to validate TRIM24 as an oncology target. This poster will describe the discovery and development of a series of novel and cellular potent dual TRIM24/BRPF bromodomain inhibitors. A combination of approaches were employed for hit-finding, including; virtual screening, assembling of an acetyl-lysine mimetic library, as well as an HTS screen which led to the identification of a lead series. X-ray crystallography guided further optimization of this series towards single-digit nM potencies. An in-vitro TRIM24 ALPHA screen and cellular target engagement assays were developed and employed to further optimize the series resulting in IACS-9571, the first reported cellular potent TRIM24 inhibitor (Kd = 0.3 nM) which displaces endogenous TRIM24 from chromatin in a cellular target-engagement assay (EC50 = 16 nM). These compounds also bind to the bromodomains of BRPF1, 2, and 3. Work is on-going to unravel the biological activity of this series as potential therapeutic treatments for oncology.

12:45 Session Break

1:00 Luncheon Presentation - Novel Quantitative and High Throughput Biochemical Assays that Enable Discovery and Optimization of Inhibitors for Epigenetic Targets 
Daniel K Treiber, Vice President, R&D, DiscoveRx Corporation
There are 57 bromodomains contained in 41 different proteins; however, few small molecule bromodomain inhibitors have been reported. One primary factor limiting the discovery of new inhibitors is the absence of a comprehensive biochemical bromodomain screening platform. Here we describe the application of proven competitive binding assay technology (KINOMEscan) to the development of quantitative ligand binding assays for human bromodomains (BROMOscan). We have developed a carefully validated assay panel that covers >50 percent of the human bromodomain family, and this panel is suitable for HTS, selectivity profiling and quantitative affinity (Kd) assessment. We have used this panel to discover that several clinical kinase inhibitors are also potent bromodomain inhibitors, which suggests rationally designed polypharmacology strategies for the development of more efficacious targeted cancer therapies. A derivative technology currently in development for the ultrasensitive readout of protein methyltransferase enzyme activity shall be described as well.  

1:40 Session Break


1:50 Chairperson’s Opening Remarks

Dafydd Owen, Ph.D., Associate Research Fellow, Medicinal Chemistry, Biotherapeutics Worldwide R&D, Pfizer

2:00 Role of BRD4 and SWI/SNF in the Maintenance of Acute Myeloid Leukemia

Chris Vakoc, M.D., Ph.D., Assistant Professor, Cold Spring Harbor Laboratory

Our lab has employed negative-selection shRNA screening to identify chromatin regulator dependencies in a mouse model of acute myeloid leukemia. These studies have identified Brd4 and SWI/SNF as among the top dependencies in this disease, which exhibit several desirable properties for therapeutic targeting. Recent work will be presented that seeks to understand the molecular mechanism of these chromatin regulators that underlies their role in cancer maintenance.

2:30 Targeting NUT Midline Carcinoma, a Disease of Aberrant Chromatin Readers

Christopher A. French, M.D., Associate Professor, Department of Pathology, Harvard Medical School; Assistant Professor, Pathology, Brigham and Women’s Hospital

I will first discuss the basic clinical aspects of NUT midline carcinoma. I will then discuss three aspects of how BRD4-NUT, the causative oncoprotein, blocks differentiation and promotes growth of affected cancer cells: how this is dependent upon the bromodomains of BRD4, its target gene MYC, and its interacting protein, p300. I will next present recent findings that reveal the chromatin regions bound by BRD4-NUT, as well as a new interactor, NSD3, which we recently found to be a variant fusion partner of NUT in a subset of NUT midline carcinomas. Finally, I will discuss the strategies and recent progress using therapeutic small molecule BET bromodomain inhibitors.

3:00 Chemical Genetics Identifies BET Proteins as Therapeutic Targets in Facioscapulohumeral Muscular Dystrophy

Fran Sverdrup, Ph.D., Research Fellow, Center for World Health and Medicine, Saint Louis University

Muscle pathology in Facioscapulohumeral muscular dystrophy (FSHD) coincides with epigenetic de-repression of the normally silent DUX4 gene in muscle. The DUX4 transcription factor activates a cascade of inappropriate gene expression that ultimately results in muscle cell death. The mechanisms by which the genetic alterations in FSHD result in DUX4 de-repression have not been completely defined and few specific therapeutic targets amenable to small molecule drug intervention have been identified. Our chemical genetics approach has identified a key role for the bromodomain and extra-terminal domain (BET) proteins in the epigenetic switch that activates DUX4.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:10 Treating Genetically Diverse Glioblastoma with Bromodomain Inhibitors

Jialiang Wang, Ph.D., Assistant Professor, Neurological Surgery, Vanderbilt University

Glioblastoma is a genetically heterogeneous disease. Yet, a wide range of glioblastoma tumors of diverse genotypes exhibited significant sensitivity to BET bromodomain inhibitors. I will discuss in vitro and in vivo activities of BET bromodomain inhibitors in glioblastoma primary samples. Molecular mechanisms underlie the oncogenic activities of BET proteins in glioblastoma will be discussed.

4:40 Betting on BETs for Advanced Prostate Cancer Treatment

Irfan Asangani, Ph.D., Research Investigator, Pathology, Michigan Center for Translational Pathology, University of Michigan

Maintenance of AR signaling is the most common resistance mechanism that patients with advanced prostate cancer develop after conventional hormonal treatments. Recently, selective small molecule inhibitors that target the bromodomains of BET family proteins have been shown to exhibit anti-proliferative effects in a range of malignancies. I will present our findings offering a preclinical proof of principle for the use of BET-bromodomain inhibitors that block AR signaling as a promising therapeutics in castration-resistant prostate cancer.

5:10 Interactive Breakout Discussion Groups 

These are moderated discussions with brainstorming and interactive problem solving, allowing conference participants from diverse backgrounds to exchange ideas, experiences, and develop future collaborations around a focused topic.

Developing BET Bromodomain Inhibitors 

Dafydd Owen, Ph.D., Associate Research Fellow, Medicinal Chemistry, Biotherapeutics Worldwide R&D, Pfizer

Bruce Lefker, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer Worldwide Research and Development

Lee Roberts, Ph.D., Associate Research Fellow, Medicinal Chemistry, Pfizer Worldwide Research and Development

  • Is it too easy to find BET inhibitors and BET biology?
  • What are the resulting selectivity implications for BET inhibitors?
  • Do BET inhibitors guide us into novel chemotypes for other bromodomains?
  • What are the prospects for other bromodomain inhibitors and working out their phenotypes?

Unintended Consequences and Pharmacology of Bromodomain Inhibitors 

Jialiang Wang, Ph.D., Assistant Professor, Neurological Surgery, Vanderbilt University

Peter Newham, Ph.D., Global Head, Discovery Safety, R&D Innovative Medicines, AstraZeneca

  • How should we be considering the safety profile of BET inhibitors, in view of the known roles of these proteins as co-repressors as well as co-activators?
  • How do different inhibitors interact and modulate bromodomains within the same BET molecule?
  • What are the biological consequences of this?

6:10 Welcome Reception in the Exhibit Hall with Poster Viewing

7:15 Close of Day

Thursday, October 9

7:30 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor & Associate Dean, Therapeutic Innovation, Miller School of Medicine, University of Miami

8:10 Targeting BET Bromodomains for Cancer Treatment

Bernard Haendler, Ph.D., Senior Scientist, Global Drug Discovery, Bayer Pharma AG

BRD4 belongs to the BET bromodomain family and represents an interesting target for the treatment of various pathologies, including cancer. Pharmacological in vitro and in vivo data on the activity of potent, selective BET inhibitors in tumor cell lines and in xenografts will be presented. In addition, the impact of individual point mutations in the BRD4 bromodomain on inhibitor and acetylated histone peptide binding will be discussed.

8:40 Epigenetic Control of T-Cell Biology

Jose M. Lora, Ph.D., Executive Director, Preclinical Sciences, Constellation Pharmaceuticals

In my talk I will discuss some of our research, elucidating how chromatin regulators and epigenetic factors are intimately involved in T-cell lineage commitment and function, and how their functional inhibition could lead to novel therapeutic opportunities.

9:10 Inhibition of BET Bromodomain Proteins in Solid Tumors

Anastasia Wyce, Ph.D., Investigator, R&D Oncology, GlaxoSmithKline

BET (bromodomain and extra-terminal) family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in a number of hematologic cancer models, partially through down-regulation of the critical oncogene, MYC. We hypothesized that BET inhibitors will similarly regulate expression of MYC family genes (MYC, MYCN, MYCL1) in solid tumor models characterized by MYC family amplification or over-expression. In the current study, we describe the activity of GSK BET inhibitors (I-BETs) in various pre-clinical solid tumor models and discuss the role of MYC gene silencing in the observed phenotypes.

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


10:30 Multifocal Defects in the Hematopoietic and Lymphoid Compartments in Mice Dosed with a Broad BET Inhibitor

Dong Lee, Ph.D., Scientist, Safety Assessment, Genentech

Several publications have shown bromo and extra terminal (BET) proteins to be attractive targets for therapeutic intervention in several human diseases. However, the safety profile of BET inhibition is largely unknown. Our study shows that mice treated with JQ1, a broad BET small molecule, at efficacious concentrations develop multifocal defects in the lymphoid and immune cell compartments. In addition JQ1 at higher concentrations are not tolerated. This toxicity study establishes a baseline safety signal for JQ1 and begs the question of whether these findings are related to specific BET isoform inhibition or caused by secondary pharmacology from JQ1.

11:00 Bromodomain and ExtraTerminal (BET) Domain Inhibitors Induce a Loss of Intestinal Stem Cells and Villous Atrophy

Peter Newham, Ph.D., Global Head, Discovery Safety, R&D Innovative Medicines, AstraZeneca

BET domain epigenetic reader proteins play a role in controlling the expression of genes that regulate cellular differentiation and proliferation and phenotype maintenance (eg, cMyc) and are frequently modified in cancer; hence BET modulators are being explored as potential therapeutics in a number of tumor settings. In addition to regulating tumor cell viability, BET inhibitors are also associated with gastrointestinal toxicity, though the molecular and cellular mechanisms behind this toxicity have yet to be elucidated. We have found that BET inhibitors induce a dose-limiting duodenal villous atrophy in vivo, accompanied by inappetence and body weight loss. Ex-vivo cultures of intestinal organoids confirm that villous atrophy occurs with multiple chemical classes of BET domain inhibitors and that their toxicity is driven by their primary pharmacology. Intriguingly, the intestinal atrophy occurs in the absence of a proliferative block, and in the presence of cMyc, suggesting that the intestinal effects are not mediated by cMyc inhibition as may have been assumed. We find instead that BET domain inhibitors induce a rapid loss of intestinal stem cells, suggesting that it is a loss of stem-cell self renewal leading to crypt loss and dose-limiting duodenal toxicity.

11:30 Enjoy Lunch on Your Own

1:00 pm Plenary Keynote Program 

Chas BountraChas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford

Martin TolarMartin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.

Andrew L. Hopkins, Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee

2:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Close of Conference

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