2017 Archived Content
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 5th Annual Targeting the Ubiquitin Proteasome System conference will once again gather an interdisciplinary collection of leaders working to advance the rapidly expanding field of UPS drug discovery.
Final Agenda
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Tuesday, September 26
7:00 am Registration Open and Morning Coffee
7:55 Chairperson's Opening Remarks
Ingrid E. Wertz, M.D., Ph.D., Senior Scientist, Discovery Oncology and Early Discovery Biochemistry, Genentech, Inc.
8:00 Session Introduction and Remarks
Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University
8:10 FEATURED PRESENTATION: Targeted Protein Degradation by Small Molecules
Alessio Ciulli, Ph.D., Professor, 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.
8:40 Target Protein Degradation for New Therapeutics
Shaomeng Wang, Ph.D., 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.
9:10 Targeted Protein Degradation via Redirecting the Action of CRL4 E3 Ligases
Brian Cathers, Ph.D., Executive Director, Co-Leader & Head, Drug Discovery, Protein Homeostasis Thematic Center of Excellence, Celgene
Distinct cereblon binding molecules evoke different phenotypic responses yet bind the same target. Solution of the ligand bound CRBN complex provides a rationale for distinguishing “gain of function” targeting of key substrates including the transcription factors Aiolos and Ikaros, the protein kinase CK1α, or the translation termination factor GSPT1. Is it possible to harness the action of a single E3 ligase and direct its actions toward new and different substrates? Are other ligases able to be co-opted in a similar fashion?
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
KEYNOTE SESSION
10:25 KEYNOTE PRESENTATION: Covalent Inhibitors and Degraders of Challenging Targets in Cancer
Nathanael Gray, Ph.D., Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Professor, Cancer Biology, Dana-Farber Cancer Institute
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.
11:10 KEYNOTE PRESENTATION: PROTACs: The Chemical Equivalent of CRISPR
Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, 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.
11:55 Selected Poster Presentation: Induced Degradation of Bcl-xL: A Protac Approach to Target the Achilles' Heel of Senescent Cells
Xuan Zhang, Research Scientist, College of Pharmacy, University of Arkansas for Medical Sciences
12:10 Enjoy Lunch on Your Own
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson’s Remarks
Gerald Gavory, Ph.D., Head, Biology, Alma Discovery
1:55 Ubiquitin -Omics for Target Discovery in Human Disease
Benedikt Kessler, Ph.D., Professor of Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford
Mass spectrometry can now cover the proteome in the ten thousand range, and ubiquitylation can be profiled in the thousands, covering enough depth to interrogate DUB and E3 ligase substrates. The ubiquitin-specific protease USP7 was suggested as a potential drug target for Multiple Myeloma, where the treatment with small molecule USP7 inhibitors overcomes resistance to clinical proteasome inhibitors. We have utilized activity-based profiling, chemical proteomics and structural analysis to determine the potency of novel deubiquitylating enzyme inhibitors.
2:25 Developing a Quantitative Profiling Platform to Evaluate Endogenous Deubiquitinase Activity
Ingrid E. Wertz, M.D., Ph.D., Senior Scientist, Discovery Oncology and Early Discovery Biochemistry, Genentech, Inc.
Here we describe the development of an analysis platform that combines DUB ABPs with chemical multiplexing, targeted mass spectrometry, novel internal reaction standards, and a customized statistical analysis program. Our strategy allows us to quantitate changes in DUB activity across a theoretically unlimited number of samples in a high-throughput manner. We illustrate the efficacy of this technology by evaluating the activity of disease-relevant DUBs, in analyzing DUB inhibitor selectivity, and in evaluating how compounds impact DUB activity.
2:55 An Integrated Chemistry and Assay Platform to Enable and Support Ubiquitin-System Targeted Drug Discovery
Jason Brown, Ph.D., Scientific Director, Ubiquigent Ltd.
Ubiquigent is a world leading provider of ubiquitin system targeted drug discovery services. We will discuss the company’s first-in-class novel deubiquitylase targeted hit-finding chemical library DUBtarget™-001 and its characterisation employing our integrated DUB platform featuring the DUBprofiler™ screening and selectivity and REDOXprofiler™ hit triage capabilities. We will also touch on Ubiquigent’s library development plans as well as our wider ubiquitin system drug discovery capability which has delivered high-throughput screening assays to a number of clients.
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell Based Anti-Tumor Activity Superior to that of Biologicals
Tauseef R. Butt, Ph.D., 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.
4:35 Development and Further Exploitation of UbiPlex - A Proprietary Drug Discovery Platform for DUBs
Gerald Gavory, Ph.D., Head, Biology, Alma Discovery
We will describe our latest efforts and developments in targeting members of the DUB family using USp7, USP19 and new DUBs as case examples. UbiPlex delivered the first genuine and highly potent and selective inhibitors of multiple DUBs hence demonstrating the druggability and tractability of this so far refractory target class.
5:05 Interactive Breakout Discussion Groups
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below. Please click here for full details on all breakouts.
Small Molecule Immune-Oncology Drugs: Ready for First-Line Therapy?
Moderator: Tauseef R. Butt, Ph.D., 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?
Novel Targets for Cancer in the Proteostasis Space
Moderator: Benedikt Kessler, Ph.D., Professor of Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford
- Biological insights into the Ubiquitin Proteasome System pathway
- Target validation approaches for novel proteostasis targets
- Emerging proteostasis targets
6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)
7:10 Close of Day
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Wednesday, September 27
7:30 am Registration Open and Morning Coffee
8:00 Chairperson’s Remarks
Benedikt Kessler, Ph.D., Professor, Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford
8:05 Mining the Deubiquitinase Family for Novel Drugs Utilizing FORMA’s Drug Discovery Engine
Stephanos Ioannidis, Ph.D., 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. Early chemistry activities exploited use of automated parallel synthesis for confirmed chemical matter, applying computational and crystallographic insights into structurally novel series as well as DUB hopping chemical scaffolds across the target family. As part of a fully integrated R&D team, FORMA engages key collaborators and collaborative networks to assist in the interrogation of biological hypotheses, target validation and selection of preferred mechanisms of action for advancement. FORMA’s novel approach to DUBs resulted in the identification of a novel chemical series that potently inhibits USP7.
8:35 Targeting Ubiquitin-Like Protein Activation
Lawrence Dick, Ph.D., Director, Biochemistry, Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co.
Pevonedistat (aka TAK-924 or MLN4924) is an inhibitor of the NEDD8 activating enzyme (NAE) currently in a Phase II trial for patients with higher-risk MDS, CML and low-blast AML (NCT02610777). Pevonedistat resembles the nucleotide substrate of NAE and it inhibits NAE by a mechanism termed “substrate-assisted inhibition” in which the NAE-NEDD8 thioester form of the enzyme catalyzes formation of a NEDD8-pevonedistat adduct that remains tightly bound to the enzyme. The activating enzymes for UBL conjugation pathways share a common enzymatic mechanism so that in principle, substrate-assisted inhibition can be applied to ubiquitin, SUMO, and the other UBL conjugation pathways. In practice, we have discovered a specific inhibitor of ubiquitin activation, TAK-243 (aka MLN7243), and a SUMO activating enzyme specific inhibitor, ML-792.
9:05 Selected Poster Presentation: Evaluation and Characterization of Small Molecule Inhibitors of Deubiquitinating Enzyme USP14 as Potential Anti-Cancer Agents
Stina Lundgren, Ph.D., Senior Research Scientist, Medivir AB
9:20 Selected Poster Presentation: Targeting Deubiquitinases (DUBs) in Lung Cancer Using Activity Based Protein Profiling (ABPP)
Shikha Mahajan, Research Scientist, Moffitt Cancer Center
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 HECT E3 and RBR E3 Ligases as Drug Targets to Treat Cancer and Neurodegenerative Diseases: Basic Science and New Screening Technologies
Alexander Statsyuk, Ph.D., 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.
10:50 Inhibition of an E2/E3 Protein-Protein Interaction as a Novel Strategy to Interfere with E3 Ligase Activity
Kamyar Hadian, Ph.D., Principal Investigator & Head, Assay Development and Screening Platform, HelmholtzZentrum München
This lecture will give insights into the discovery of a novel E2/E3 protein-protein interaction small molecule inhibitor that we were able to validate and characterize in a variety of biochemical as well as cell-based assays including primary mouse and human cells. More importantly, we can show that this first-in-class inhibitor is effective in preclinical autoimmune mouse models for psoriasis as well as rheumatoid arthritis.
11:20 Enjoy Lunch on Your Own
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Close of Conference
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