Targeting Epigenetic Readers and Chromatin Remodelers

2015 Archived Content

One of the most recent and exciting areas of discovery research centers around targeting chromatin modifying proteins, particularly those responsible for the recognition of the histone code written in acetyl and methyl marks. With several clinical trials underway, and discovery programs initiated throughout the biopharma landscape, particular interest has been given to targeting the bromodomain family of proteins across a diverse range of therapeutic indications. Advances in inhibitor development - allowing for individual and polypharmacological targeting of bromodomain proteins, as well as preclinical and clinical studies, are providing a better understanding as to the significant therapeutic potential of targeting chromatin-associated proteins.

Cambridge Healthtech Institute's third annual Targeting Epigenetic Readers and Chromatin Remodelers meeting will once again unite academic and industry researchers for the development of chemical probes, to discuss advances in preclinical and clinical programs, and ultimately to further our understanding of the therapeutic opportunities associated with targeting reader domains and chromatin remodelers.

Final Agenda

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Tuesday, September 22

7:00 am Registration and Morning Coffee

8:00 Chairperson’s Opening Remarks

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

8:10 New Chemical Tools Targeting BET Bromodomains and Advances in the Bump and Hole Approach

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

In my talk I will present recent developments from our lab at targeting BET bromodomain proteins using chemical tools, including advances and optimization of our bump and hole approach to introduce controlled selectivity of BET bromodomain chemical probes.

8:40 Specific BET Bromodomain Inhibitors to Treat Disease

Chris Burns, Ph.D., Laboratory Head, Chemical Biology Division, Walter and Eliza Hall Institute, Australia

We have identified chemically novel scaffolds that bind to bromodomain proteins. We prepared a series of compounds based on these chemical scaffolds and profile the compounds for both bromodomain inhibition and activity against AML, to generate compounds with improved selectivity compared to known inhibitors.

9:10 Bromodomain Inhibitors in Cancer Therapy

Jun Qi, Ph.D., Lead Scientist, Medical Oncology, Dana-Farber Cancer Institute

In cancer, epigenetic proteins are intensely studied targets for drug discovery owing to the general view that it is not just the DNA sequence that is altered in epigenetics-based diseases. We have been focusing on developing small molecule inhibitors of the BET (for bromodomain and extraterminal domain) epigenetic readers, which recognizes the acetylated lysine side chain on histones. We designed and synthesized a thienodiazepine based small molecule inhibitor JQ1, which exhibits excellent inhibition against the BET subfamily with low nanomolar binding potency. We further utilized it to study the mechanisms underlying the response to BET inhibitor at a transcriptional level in different epigenomic contexts. We have also developed chemistry strategy and assay platform to further understand the role of bromodains outside BET family.

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

10:25 Fragment-Based Design of Potent and Selective CREBBP Bromodomain Ligands

Amedeo Caflisch, Ph.D., Professor and Chair, Computational Structural Biology, Department of Biochemistry, University of Zurich

We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughput docking with a hit rate of 12%. Guided by the docked pose and molecular dynamics simulations, one of the two hits was improved by medicinal chemistry into a low nanomolar lead with very good ligand efficiency and selectivity as measured by isothermal titration calorimetry. The crystal structures of a nanomolar derivative has validated the pose of the hit obtained in silico. Some of the derivatives inhibit proliferation of a small subset of leukemia cell lines.

10:55 Design and Development of Novel BET Bromodomain Inhibitors

Shaomeng Wang, Ph.D., Director, Center for Discovery of New Medicines; Warner-Lambert/Parke-Davis Professor, Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center

I will discuss the design, synthesis, characterization and development of novel small molecule drugs targeting bromodomain-containing proteins for the treatment of human cancer.

11:25 Novel Chemical Probes Targeting Bromodomains

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

During this lecture I will discuss how a small molecule, PFI-3, dissected knock down studies and truly identify the target required for efficacy drugging SWI/SNF mediated cancers. I will also discuss PFI-4, which is a new probe for the bromodomain BRPF1. Finally I will share the development of a new probe, PFI-5, an extension to our PFI-3 story.

11:55 Proteomics & Patients

Yingming Zhao, Ph.D., Professor, University of Chicago

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

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

1:50 Chairperson’s Remarks

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

2:00 CNS Effects of BET Bromodomain Inhibitors

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

We have 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.

2:30 Discovery of Scaffold/Platform for the Development of Dual PI3K/BRD4 Inhibitors

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

Key in vitro and animal proof-of-concept efficacy studies will be presented for the lead compound SF2523. Moreover, the recently described epigenetic kinome adaptation response which encodes targeted therapeutic resistance in cancer is blocked by Brd4 BET inhibitors and represents a novel strategy to augment antitumor effects of targeted therapies including PI-3 kinase inhibitors in vitro and in vivo.

3:00 *Late Breaking Research* - Inhibition of SMARCA2: A Novel Target for SMARCA4-Deficient Lung Adenocarcinoma

H. Nikki March, Ph.D., Target Validation Lead Scientist, Cancer Research UK Manchester Institute

In this work, we developed a bioinformatics pipeline based on the collateral vulnerability hypothesis to integrate several sources of public data and identify novel targets to form the basis of a new drug discovery project. Genomic data from TCGA was integrated with phenotypic data extracted from Mousemine, Flymine and Wormbase to identify loss-of-function aberrations in genes from families with essential predicted function. The pipeline has been applied to several cancer types, and as a result, a drug discovery project has been initiated against SMARCA2 in SMARCA4-deficient lung adenocarcinoma. SMARCA4 is a bromodomain-containing transcriptional co-activator within the multi-subunit SWF/SNF complex, which also possesses helicase and ATPase activities and functions to alter chromatin structure. SMARCA4-deficient cell lines harbour abrogating mutations, and previous studies have demonstrated that knockdown of SMARCA2, its functional paralogue, in SMARCA4-deficient cell lines results in reduced cellular proliferation and survival. Moreover, SMARCA2 has been shown to be inactivated by epigenetic silencing in a proportion of human tumours. The collateral vulnerability hypothesis was tested in a panel of lung adenocarcinoma cell lines with SMARCA2- and/or SMARCA4-deficiencies. Experiments investigating the effect of siRNA knockdown in these gene-deficient cell lines confirmed both our hypothesis and the published data. A fragment screen against the bromodomain of SMARCA2 generated a high 'ligandability' index, suggesting that this target is druggable. In conclusion, SMARCA2 has been validated by our work and other groups as a target in SMARCA4-deficient lung adenocarcinoma. Future work will focus on elucidating the role of the bromodomain and the ATPase domain in SMARCA2/4 activity. We are also actively pursuing the identification of small molecule inhibitors of SMARCA2, and an HTS has been undertaken against a library of >700 million compounds in a DNA-encoded library to identify novel hit matter that may ultimately be developed for therapeutic value.

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

4:10 Synthetic Lethal Approaches to ARID1A-Mutated Ovarian Cancers

Rugang Zhang, Ph.D., Associate Professor, The Wistar Institute

The Zhang laboratory strives to uncover novel epigenetic strategies for developing cancer therapeutics. Recent work from his laboratory will be presented that investigates the molecular basis and therapeutic opportunities for human cancers with mutations in the components of the SWI/SNF chromatin-remodeling complex.

4:40 Discovery of Cancer Drug Targets by CRISPR-Cas9 Screening of Protein Domains

Junwei Shi, Research Scientist, Vakoc Lab, Cold Spring Harbor Laboratory

CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. To improve CRISPR-Cas9 performance in genetic screening, we target CRISPR-CaS9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

5:10 Interactive 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.

Enhancing Bromodomain Inhibitor Discovery

Moderator: Amedeo Caflisch, Ph.D., Professor and Chair, Computational Structural Biology, Department of Biochemistry, University of Zurich

Non-BET bromodomains: Any (strong) evidence for pharmaceutical relevance?
Reliability and reproducibility of binding assays for bromodomains; artifacts and false positives of competition binding assays; false negatives of thermal shift assay
How to improve stability of bromodomains that are difficult to handle, e.g., ATAD2
Practical suggestions for growing crystals of "difficult" bromodomains
Cellular assays to demonstrate target engagement

Examining the Basic Actions of BET Proteins

Moderator: Eric Campeau, Ph.D., PMP, Director of Biology, Zenith Epigentics

Actions of BET proteins and specifically BRD4 in mediating actions of Pol II that differentiates it from BRD2/3 activity
Actions of BET proteins in selective vs. pan inhibition
Actions of BET proteins in inflammation

Clinical Considerations for Targeting Bromodomains

Moderator: Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

Identification of predictive biomarkers of BET response. What has been the progress and where are we going in the clinic?
Combination studies: Much has been published, but what are the best opportunities and underlying mechanisms of action?
Do bromodomain-1 or bromodomain-2 specific inhibitors provide advantages over pan-BET bromodomain inhibitors?
What advantages do ‘next-generation’ pan-BET inhibitors provide?
What are the best opportunities for BET inhibitors in solid tumors? Again, much has been published, but what really stands out from a clinical perspective? Related to this, what are clinically tolerable doses of BET inhibitors?
What are the most interesting opportunities for BET inhibitors in non-oncology indications, if any? Related to this, what are the clinical dose-limiting toxicities of BET inhibitors and how does this limit with non-oncology indications?

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

7:15 Close of Day

Day 1 | Day 2 | Download Brochure

Wednesday, September 23

7:30 am Registration and Morning Coffee

8:00 Chairperson’s Remarks

Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

8:10 *Late Breaking Research* - Novel, Small Molecule BET Inhibitors for Treatment of Cancer

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

BET family of epigenetic readers, including BRD2, 3 and 4 have been identified as therapeutic targets in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. BRD4-NUT mutations are oncogenic and BET Inhibitors have been shown to be efficacious in vivo resulting in improved overall survival. Therefore, we are developing three different series of novel, potent BET family inhibitors for the treatment of haematological as well as solid tumors. Several compounds from all three series showed strong in vitro potency against BRD4 which was comparable to or stronger than OTX-015 and iBET-762, which are BET inhibitors in clinical trials. Multiple co-crystal structures have been solved in-house and were extensively used in optimization of this novel scaffold. JBET-050 showed strong effect in inducing G1 arrest of cancer cells with a concomitant, dose-dependent increase in the mRNA and protein expression of p21. Treatment with JBET-050 also resulted in a decrease of c-Myc and Bcl-2 at mRNA as well as protein levels. JBET-050 was very selective for BET family of proteins as observed from bromoscan profiling. JBET-050 showed excellent oral bioavailability in mouse and rat and good exposure in plasma as well as in tumor. In MV-4-11 xenograft model, oral administration of JBET-050 resulted in much stronger tumor growth inhibition than iBET-762 at comparable doses. Further studies to understand the toxicity profile of JBET-050 are underway. In addition, several potent BRD4 inhibitors having good oral availability have also been identified from different series and further profiling of these compounds is in progress. These BET inhibitors will have promising therapeutic benefit in treating cancer either as standalone therapy or in combination with other standard of care agents.

8:40 Preclinical Activity of a Novel BET Bromodomain Inhibitor

Phillip Liu, Ph.D., Associate Directory, Applied Technology, Incyte Corporation

BET bromodomain proteins are epigenetic readers that have been implicated in the development and progression of various diseases including cancer and inflammation. I will present data describing a novel clinical compound INCB54329 that potently and selectively inhibits BET proteins. Activity of INCB54329 in pharmacological models of cancer as single agent and in combination with approved and novel agents will be discussed.

9:10 Efficacy of BET Bromodomain Inhibition in Hematological Tumor Models

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

A novel BET inhibitor with strong in vitro and in vivo efficacy in acute myeloid leukemia, multiple myeloma and lymphoma models will be presented.

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

10:25 Targeting Hematologic Malignancies with the BET Bromodomain Inhibitor CPI-0610

Robert J. Sims III, Ph.D., Executive Director, Biology, Constellation Pharmaceuticals, Inc.

The BET family of proteins control the expression of key oncogenic pathways through its regulation of RNA polymerase II transcript elongation. CPI-0610 is a potent and selective BET bromodomain inhibitor currently in phase 1 clinical trials for diverse hematologic malignancies. Interim clinical findings from these phase 1 studies will be discussed along with our refined patient selection strategies.

10:55 *Late Breaking Research* - Preclinical Characterization of ZEN-3694, a Novel BET Bromodomain Inhibitor for the Treatment of Hematological and Solid Tumor Malignancies

Eric 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.

11:25 Enjoy Lunch on Your Own

12:55 pm Plenary Keynote Program: