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
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.
Wednesday, April 4
12:30 pm Registration
12:45 Dessert Break in the Exhibit Hall with Poster Viewing
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
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.
Topic: Novel Targets for Cancer in the Proteostasis Space
Moderator: Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston
- Biological insights into the Ubiquitin Proteasome System pathway
- Target validation approaches for novel proteostasis targets
- Emerging proteostasis targets
Topic: Small Molecule Immune-Oncology Drugs: Ready for First-Line Therapy?
Moderator: Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.
- Can biomarkers be developed to identify treatable patients and monitor therapy?
- Can they be combined with other immune-oncology drugs and/or drugs that act directly on the tumor to achieve maximum efficacy?
- How can the unleashed immune effect be tempered to minimize side effects?
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
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 ABOver the years, USP14 has been reported to regulate the stability of a variety of proteins as well as modulating signal transduction in multiple cellular pathways, thereby effecting a range of cellular processes including Wnt-signaling and autophagy. USP14 aberrant expression and activity has been suggested to play an important role in tumorigenesis and neurodegenerative diseases. As part of Medivir DUB drug discovery efforts targeting DUBs, we have characterized a set of small molecule USP14 inhibitors We present data evaluating the effect of these USP14 inhibitors on cellular proliferation and Wnt signaling and compare them to the effect of siRNA knockdown of USP14.
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
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
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 CRL4CRBN 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