Cambridge Healthtech Institute’s Inaugural

Ubiquitin Proteasome System Inhibitors

Discovery and Development of Small Molecules Targeting DUBs and Ligases

April 4-5, 2018 | Hilton Bayfront | San Diego, California

The ubiquitin proteasome system (UPS) is an essential and highly regulated mechanism operating to tightly control intracellular protein degradation and turnover. Advances in our understanding of the role and molecular mechanisms of UPS components in disease and the development of high-quality chemical tools and novel inhibitors have taken the Ubiquitin Proteasome System from an improbable target class, to one of the most robust and exciting arenas for the discovery of novel drugs. Over the past years, we have seen the generation of several DUB inhibitors poised for clinical development, novel approaches and inhibitors disrupting the protein-protein interactions of E3 ligases, hijacking the UPS for targeted protein degradation, and targeting the immunoproteasome.

Cambridge Healthtech Institute’s Inaugural Ubiquitin Proteasome System Inhibitors conference will gather an interdisciplinary collection of leaders working to advance the rapidly expanding field of UPS drug discovery.

Final Agenda

Wednesday, April 4

12:30 pm Registration

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

HIJACKING THE UPS FOR TARGETED PROTEIN DEGRADATION

1:30 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

1:40 Target Protein Degradation for New Therapeutics

Shaomeng Wang, PhD, Warner-Lambert/Parke-Davis Professor, Medicine; Professor, Medicine, Pharmacology and Medicinal Chemistry; Director, Center for Therapeutics Innovation, University of Michigan

Recently, a new small-molecule approach has been employed to target degradation of BET proteins through the design of bifunctional, Proteolysis-Targeting Chimera (PROTAC) molecules. Based upon our new classes of highly potent small-molecule BET inhibitors, we have designed and optimized highly potent and efficacious small-molecule degraders of BET proteins. We have performed critical and extensive evaluation of our BET degraders for their therapeutic potential and mechanism of action in models of acute leukemia and solid tumors.

2:10 PROTACs: The Chemical Equivalent of CRISPR

Dan Bondeson, Research Scientist, Crews Lab, Yale University

Induced protein degradation offers several advantages over traditional inhibition strategies and has emerged recently as a potential therapeutic option. For the past 16 years, we have helped develop this fast growing field, shepherding our initial chemical biology concept into a drug development strategy that is on the verge of clinical validation. PROTACs with high target selectivity, potency, and oral bioavailability will be discussed as well as a system to address the ‘PROTACability’ of particular E3 ligases.

2:40 Covalent Inhibitors and Degraders of Challenging Targets in Cancer

Dennis Dobrovolsky, Research Scientist, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

This presentation will discuss new pharmacological strategies towards targeting kinases and other targets. Small molecules capable of inducing protein degradation through the recruitment of E3 ligases will be discussed with a focus on kinases. A general approach for identifying the most easily degradable kinase targets will be presented. Chemical design principles for developing degraders will be discussed. New approaches for developing covalent kinase inhibitors will also be discussed.

3:10 Protein Ubiquitination in Immune Homeostasis and Dysregulation

Yun-Cai Liu, PhD, Professor La Jolla Institute for Allergy and Immunology

Effective immune responses in our body are critical in defending invading pathogens, whereas such responses are balanced by immune tolerance mechanisms to prevent from attacking our own tissues. Loss of such balance could result in excessive tissue damage or malignant tumor formation. Our research for the last two decades has documented that E3 ubiquitin ligases play an essential role in lymphocyte activation and tolerance induction. We previously showed that the E3 ubiquitin ligase VHL-hypoxic inducing factor (HIF) pathway plays a key role in controlling the stability and function of regulatory T cells by modulating interferon-g production. We recently extended our studies to other cell types including innate lymphoid type 2 cells, and found that the VHL-HIF axis is important in regulating their development and function via switching the cellular glucose metabolism from oxidative phosphorylation to hypoxic glycolysis during lung inflammation. The latest results of our on-going research will be presented in this meeting. The anticipated results will provide us with a unique opportunity in targeting the E3 ligases in different cell types for potential therapeutic intervention of human inflammatory diseases and cancer.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Targeted Protein Degradation by Small Molecules

Andrea Testa, PhD, Research Scientist, Ciulli Lab, Chemical & Structural Biology, School of Life Sciences, University of Dundee

The application of small molecules to induce selected protein degradation is emerging as a transformative new modality of chemical intervention in drug discovery. We have previously shown that linking a VHL ligand that we had discovered with a pan-BET inhibitor creates highly selective PROTAC molecule MZ1. MZ1 triggers preferential intracellular degradation of Brd4, leaving the homologous BET members untouched, and exhibits greater anti-proliferative activity in leukemia cell lines than pan-BET inhibition.

5:00 Selected Poster Presentations

Ubiquitin Carboxyl-terminal H-L5 Inhibitor Diminishes TGFbeta-1 Signaling and Ameliorates Pulmonary Fibrosis

Yutong Zhao, MD, PhD, Associate Professor of Medicine and Cell Biology, Co-director of Acute Lung Injury, Center of Excellence Department of Medicine University of Pittsburgh School of Medicine

DYRK2, a Novel Therapeutic Target in 26S Proteasome Dependent Neoplastic Malignancies

Sourav Banerjee PhD, Post-doctoral Scholar, Department of Pharmacology, University of California San Diego

5:30 Breakout Discussions

6:15 End of Day

6:30 Dinner Short Courses*

*Separate registration required.

Thursday, April 5

8:00 am Breakfast Presentation: Improvements in NMR Approaches to Fragment Based Screening

Donna Baldisseri, Senior Applications Scientist, Bruker BioSpin

FBDD is a powerful search engine for identification of fragments that bind to disease relevant target proteins ultimately leading to drug candidates. NMR-based FBDD screening requires compound library validation, preparation of hundreds of samples per campaign, automated acquisition, processing of thousands of spectra, and their analysis for binding assessment. Here is described the streamlined solutions offered by Bruker, automating this pipeline to improve the speed and productiveness of FBDD screening for the pharmaceutical industry.

8:45 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:50 Plenary Keynote Introduction

Chris Petersen, CTO, Scientist.com

8:55 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine

Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

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

DESIGN AND DEVELOPMENT OF NOVEL DEUBIQUITINASE (DUB) INHIBITORS

10:40 Chairperson’s Remarks

Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.

10:45 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell-Based Anti-Tumor Activity Superior to That of Biologicals

Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.

In immune competent animal models, USP7 inhibitors are potent anti-tumor agents, not only blocking tumor growth but also eliminating tumor metastasis. These results constitute the first example of a small molecule single agent that works by targeting both the tumor itself and the host immune system and also by eliminating tumor metastasis. In animal models, the USP7 inhibitor demonstrates activity that is superior to that of PD1 and CTLA4 antibodies.

11:15 Evaluation and Characterization of Small Molecule Inhibitors of Deubiquitinating Enzyme USP14 as Potential Anti-Cancer Agents

Stina Lundgren, PhD, Associate Principal Scientist/Project Leader, Medivir AB

11:45 Bio-Techne - Your Partner in UPS-Related Research and Drug Development

Bradley Brasher, PhD, Managing Director, Boston Biochem

I will illustrate how Bio-Techne companies including Boston Biochem, Tocris, R&D Systems, Novus, and Protein Simple support the research and development of small molecule deubiquitinase inhibitors and PROTACs compounds. Additionally, I will detail how Boston Biochem can provide custom proteins and proteomics services for building and monitoring in vitro assays.

12:00 pm Mining the Deubiquitinase Family for Novel Drugs Utilizing FORMA’s Drug Discovery Engine

Stephanos Ioannidis, PhD, Head, Early Portfolio, FORMA Therapeutics

The deubiquitinating enzymes (DUBs), by their reversal of the ubiquitination/polyubiquitination process, are key enzymes regulating protein homeostasis. As such, modulators of DUB function have the potential to be important therapeutics in oncology, immunology, neurodegenerative and other medical disorders involving pathological or dysregulated proteins. FORMA Therapeutics deploys multiple drug discovery screening platforms to explore broad target families on scale. Panels of functional cellular and enzymatic assays, including related target family selectivity screens, were established to mine the DUBome for novel chemical matter.

12:30 Enjoy Lunch on Your Own

1:30 Dessert Break in the Exhibit Hall with Poster Awards

INSIGHTS INTO DEUBIQUITINASE ENZYMES AND INHIBITORS

2:15 Chairperson’s Remarks

Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.

2:20 DUB Inhibitors in Syngeneic Cancer Models and in Preclinical Studies

Wayne W. Hancock, M.D., Ph.D., Professor, Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

When it comes to trash talking about cells, there are lots to gossip about and reasons to do so. I will briefly review the key interactions between the trash collectors and the trash recyclers within cells, and how this has gone from esoterica to essential in the era of immune-oncology. DUBs help determine the outcomes of checkpoint blockade inhibition and are key to the functions of each of the main players in the immune response to cancer. While the effects of DUB inhibitors in reductionist xenograft models are salutary, the more relevant actions in syngeneic tumor models and in patients involve balancing the effects of DUB inhibitors on the immune system with their effects on tumor cells, and these are not things that can be predicted by their structures or staring at their ADME/tox profiles.

2:50 USP7-Specific Inhibitors Target and Modify the Enzyme's Active Site via Distinct Chemical Mechanisms

Irina Bezsonova, PhD, Assistant Professor, Department of Molecular Biology and Biophysics, University of Connecticut

USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin.

3:20 Chemical Libraries to Unlock Deubiquitylase (DUB) Targeted Drug Discovery

Jason Brown, PhD, Scientific Director, Ubiquigent Ltd

Ubiquigent is a world leading provider of ubiquitin system targeted drug discovery tools and services. Within the ubiquitin signalling cascade the deubiquitylase (DUB) enzyme family offers a deep seam of drug target opportunities addressing an array of therapeutic areas. We will discuss Ubiquigent’s commercially accessible first-in-class novel DUB targeted hit-finding chemical library DUBtarget™-001 and its characterisation employing our integrated service platforms featuring the DUBprofiler™ screening and selectivity and REDOXprofiler™ hit triage capabilities.

3:50 Refreshment Break

TARGETING THE PPIs OF E3 LIGASES

4:20 HECT E3 and RBR E3 Ligases as Drug Targets to Treat Cancer and Neurodegenerative Diseases: Basic Science and New Screening Technologies

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

E3 ligases (>600 known) are the key mediators of protein degradation pathways, and E3 ligase inhibitors or activators are promising drug leads. In addition, E3 ligases can be executors that mediate the degradation of PROTAC targets. In this presentation, we specifically discuss emerging biochemical mechanisms and biological roles of HECT and RBR E3 ligases, their therapeutic potential to treat cancers and neurodegenerative diseases, and current screening technologies to discover initial drug leads for this class of drug targets.

4:50 Redirecting the Cereblon-CRL4 Ubiquitin Ligase With Cereblon Modulator Compounds

Mary Matyskiela, PhD, Senior Scientist, Structural and Chemical Biology, Celgene

Cereblon modulators bind cereblon to confer differentiated substrate specificity to the CRL4^CRBN E3 ubiquitin ligase. CC-220 is a cereblon modulator in Phase II clinical development that exhibits improved degradation of Ikaros and Aiolos. CC-885, a cereblon modulator with potent anti-tumor activity, mediates the cereblon-dependent ubiquitination and proteasomal degradation of the translation termination factor GSPT1. Crystallographic studies of the cereblon-DDB1-CC-885-GSPT1 complex revealed that GSPT1 binds cereblon and CC-885 through a surface turn containing a glycine residue at a key position. Mutational analysis and modeling demonstrate that the cereblon substrate Ikaros depends upon a similar structural feature for cereblon binding. These findings define a structural degron underlying cereblon ‘neosubstrate’ selectivity, and pave the way for the development of new cereblon modulators.

5:20 Cep78, a Novel Inhibitor of the HECT E3 Ubiquitin Ligase EDD-DYRK2-DDB1DCAF1

William Tsang, PhD, Research Unit Director, Cell Division and Centrosome Biology, Montreal Clinical Research Institute

EDD-DYRK2-DDB1DCAF1 is a multi-subunit HECT E3 ubiquitin ligase whose physiological functions are not fully understood. We found that EDD-DYRK2-DDB1DCAF1 is present at the centrosome, an organelle crucial for cell division, and that its enzymatic activity is regulated by a novel centrosomal protein called Cep78 in human cells. By using a combination of biochemistry, molecular biology, and cell biology, we dissected the mechanism by which EDD-DYRK2-DDB1DCAF1 is inhibited by Cep78.

5:50 End of Conference