2nd Annual

Epigenetic Inhibitor Discovery

Chemically Modulating Gene Expression

April 21-22, 2015 

 

Epigenetic drug discovery is one of the fastest growing and potentially groundbreaking target spaces for developers. Over the past few years, a significant increase in small molecule inhibitors chemically modulating enzymatic activity of Histone Methyltransferases (HMTs), Histone Demethylases (HDMs), and disrupting interactions of the BET family bromodomains have rapidly translated into clinical investigation. Now, with apparent safety and efficacy being demonstrated in clinical trials, the opportunity to develop novel chemical tools and inhibitors against the wealth of epigenetic modifiers is ever present. 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. Join fellow drug discovery scientists for this day-and-a-half meeting that is in the first half of CHI’s larger Drug Discovery Chemistry event.


 

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

Fabrizio G., Principal Scientist, AstraZeneca


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Tuesday, April 21

7:00 am Registration and Morning Coffee


EMERGING STRATEGIES FOR DISCOVERY OF BROMODOMAIN INHIBITORS 

8:00 Chairperson’s Opening Remarks

8:10 FEATURED PRESENTATION: A Bump-and-Hole Approach to Engineer Controlled Selectivity of BET Bromodomain Chemical Probes

Alessio CiulliAlessio Ciulli, Ph.D., Reader, Chemical & Structural Biology, BBSRC David Phillips Fellow, College of Life Sciences, University of Dundee

We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in disease, and aid association of the pharmacology of BET bromodomain inhibitors to particular targets.

8:40 In silico Discovery and Experimental Validation of Selective Bromodomain Inhibitors

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

We have discovered in silico, validated by X-ray crystallography, and optimized by chemical synthesis a series of nM potent and selective ligands of the CREBBP bromodomain. Fragment-based, high-throughput docking was employed for the identification of novel scaffolds whose affinity was enhanced. The specificity and easy synthetic availability of our compounds will be useful to unravel the biological role(s) that CREBBP plays. Using the same approach, we have recently identified potent inhibitors of representatives of five different families of bromodomains.

9:10 Using Biophysics to Target Methyl
Transferases (HKMTs) with Small Molecules

Gregg Siegal, Ph.D., CEO, ZoBio

HKMTs are an important class of targets, yet it has proven challenging to develop drug-like inhibitors against them. We have used our TINS NMR technology to screen a diversity fragment collection which has lead to SPR validated, novel hit matter against for 4 HKMTs. The hits target both the SAM and substrate sites. We find differences in the small molecule binding of the HKMTs. This allows us to 1) prioritize HKMTs on ligandability, 2) redefine family relationships based on pharmacology and 3) select specific or pan-family ligands as starting points for drug development efforts.

9:40 Coffee Break


ADVANCES IN BET BROMODOMAIN INHIBITOR DEVELOPMENT 

10:05 Discovery 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

A novel thienopyranone molecular scaffold has been discovered to selectively inhibit PI3 kinase as well as the bromodomain protein BRD4. Molecular modeling studies will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions. As a cancer therapeutic this dual inhibition mechanism allows for a unique and powerful way to modulate critical components of cancer cells. Key in vitro and animal proof-of-concept efficacy studies will be presented for the lead compound SF2523.

10:35 Discovery and Development of a Potent Dual TRIM24/BRPF1 Bromodomain Inhibitor, IACS-9571, Using Structure-Based Drug Design

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

We have developed a potent cellular dual TRIM24/BRPF1 bromodomain inhibitor which will be useful for interrogating the biological role of the bromodomains of these two proteins. We employed three different approaches for finding a starting point, including; virtual screening, assembling an acetyl-lysine mimetic library, and an HTS screen which led to the identification of a lead series. Iterative use of X-ray crystallography and observation of an unexpected binding-mode guided further optimization of this series towards single-digit nM potencies.

11:05 Translating Chromatin Biology into Drug Discovery

Brian Albrecht, Ph.D., Senior Director, Medicinal Chemistry, Constellation Pharmaceuticals

There continues to be considerable interest in drugging epigenetic targets due to the profound potential to have an impact on disease. Constellation is interested in the readers, writers and erasers of histone modifications. Our drug discovery efforts towards identifying inhibitors of these therapeutic targets will be discussed.

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

12:05 pm Session Break


CHEMICALLY MODULATING DNA & HISTONE METHYLTRANSFERASES 

1:15 Chairperson’s Remarks

Brian Lohse, Ph.D., Associate Professor, Drug Design and Pharmacology, University of Copenhagen

1:20 Discovery and Development of Novel Arginine Methyltransferase Inhibitors

Richard Chesworth, Ph.D., Executive Director, Molecular Discovery, Epizyme

1:50 Discovery of a Potent and Specific Drug to Inhibit PRMT5 in Hematologic and Solid Tumors

Chenglong Li, Ph.D., Associate Professor, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Comprehensive Cancer Center

Through our lab-developed novel fragment-based drug design strategy, MLSD (multiple ligand simultaneous docking), we have optimized a class of drug-like small molecules in three iterative rounds. These PRMT5 inhibitors are potent and specific with favorable PK/PD properties. This presentation will discuss a novel lead in this series on the design process and demonstrate its efficacies in various hematologic and solid tumor models, such as lymphoma, AML and high grade astrocytomas.

2:20 Sponsored Presentation (Opportunity Available)

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

3:20 Discovery of First-in-Class Reversible Dual Inhibitors of DNA Methyltransferase and Histone Methyltransferase G9a

Julen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical Research (CIMA), University of Navarra

We have designed and synthesized a new series of small molecules that act as potent, selective and reversible DNMT and G9a inhibitors. The most potent molecules inhibit both targets in the nanomolar range (IC50<100nM) and their functional responses, in vitro cellular, clearly show the corresponding impact on their epigenetic marks (2meH3K9 and 5-methylcytosine) with EC50 values of around 100nM, thus, confirming their mode of action. Off-target profiling shows that these molecules are selective against a panel of 37 additional epigenetic targets (<50% inhibition at 10uM).

3:50 The Discovery and Characterization of A-366, a Potent and Selective Inhibitor of Histone Methyltransferase G9a

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

This talk highlights the discovery of a new class of inhibitors for G9a that are among the most potent and selective known for this methyltransferase. Physical and biological characterization of A-366, a representative compound from this class of inhibitors, has highlighted the utility of using this compound as a probe for studying G9a function. Further characterization has demonstrated efficacy of A-366 in particular models of leukemia.

4:20 Session Break


PLENARY KEYNOTE SESSION 

4:30 Plenary Keynote Introduction

Gregg Siegal, Ph.D., CEO, ZoBio

»4:40 PLENARY KEYNOTE PRESENTATION: 

Chemotype Coverage in Fragment, Phenotypic, & Deorphanization Screens

Brian K. ShoichetBrian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco

The numbing size of chemical space shouldn’t prevent us from asking what screening libraries are missing relative to what we know to be biologically relevant. I explore the impact of chemotype representation on inhibitor discovery, fragment-based screens, whole organism phenotypic screens, and screens to deorphanize enzymes and GPCRs. Each case is framed by rough calculation and illustrated by specific experimental results. The libraries that result differ as much as the goals of the screen, but specific limits and optimization strategies emerge.


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

6:30 Close of Day


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Wednesday, April 22

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.


CHEMICALLY MODULATING HISTONE DEMETHYLASES 

8:40 Chairperson’s Remarks

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

8:45 Overcoming Drug Resistance through Small Molecule Epigenetic Modulation

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

Recent results will be described that establish the use of epigenetic inhibitors to overcome the transcriptional reprogramming that facilitates drug resistant phenotypes.

9:15 Epigenetic Inhibitors are Potentially Useful Therapeutics for Acute Leukemia

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

We synthesized several potent LSD1 inhibitors and found they exhibited strong activity against MLL-rearranged leukemia cells, while these compounds are non-cytotoxic to several other tumor cells. One compound showed significant in vivo activity in a systemic leukemia mouse model without overt toxicities. The mechanistic studies of LSD1 inhibitors as well as their synergy with other epigenetic compounds against MLL leukemia are discussed.

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


TOOLS AND STRATEGIES ENABLING
EPIGENETIC DRUG DISCOVERY
 

10:30 Histone Binding Mechanisms and Specificities of PHD Fingers

Tatiana Kutateladze, Ph.D., Professor, Department of Pharmacology, Anschutz Medical Campus, University of Colorado

Plant homeodomain (PHD) fingers comprise one of the largest families of epigenetic effectors capable of recognizing PTMs (posttranslational modifications) of histones. Here, I summarize the structures and binding mechanisms of the PHD fingers that select for modified and unmodified histone H3 tails. I will compare the specificities of PHD fingers, Tudor and other histone readers, and discuss the significance of crosstalk between PTMs and the consequence of combinatorial readout for the selective recruitment of these effectors to chromatin.

11:00 Discovery of Novel Small Molecules and Small Cyclic Peptides as Chemical Tools and Inhibitors, Using DNA Encoded Peptide Libraries for HDMs and HMTs

Brian Lohse, Ph.D., Associate Professor, Drug Design and Pharmacology, University of Copenhagen

EpiDiscoverY has previously shown new strategies and is continuously searching for alternative ways to identify new tool compounds for epigenetic targets, primarily HDMs (KDM4 and KDM1) and HMTs (EHMT and PRMTs). Here we present how we have used DNA encoded peptide libraries to identify both small molecule inhibitors and recently small cyclic peptide inhibitors for KDM4 and KDM1 and for EHMT and PRMTs. The entire strategy and timeline is presented along with two new assays.

11:30 Mechanistic Characterization of PRMT5 Enzyme Complexes

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

PRMT5 methylates arginine residues on protein substrates. Many different PRMT5 complexes have been described and different complexes are suggested to have different substrate preferences. We have enzymatically characterized PRMT5 complexes and will compare and contrast mechanism of action and inhibition and suggest a potential regulation mechanism.

12:00 pm Close of Track


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