Discovery on Target
Discovery on Target Mobile Header

Targeting the Ubiquitin Proteasome System Header


The ubiquitin proteasome system (UPS) is an essential and highly regulated mechanism operating to tightly control intracellular protein degradation and turnover. While the concept of targeting specific components of the UPS to modulate protein degradation has been around for some time now, recent advances in our understanding of the role and molecular mechanisms of UPS components in disease – mainly DUBs and E3 ligases, the development of high-quality chemical tools and novel inhibitors, as well as preclinical studies demonstrating chemical tractability and therapeutic potential – have dramatically 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. Indeed, over the past year, 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 and UPS-mediated degradation of target proteins.

Cambridge Healthtech Institute’s fourth annual Targeting the Ubiquitin Proteasome System will once again gather an interdisciplinary collection of leaders working to advance the rapidly expanding field of UPS drug discovery.

Final Agenda


RECOMMENDED ALL ACCESS PACKAGE:

• September 19 Short Course: Phenotypic Screening and Chemical Probe Development

• September 19 Short Course: RNA as a Small Molecule Drug Target

• September 20-21 Conference: Targeting the Ubiquitin Proteasome System

• September 21-22 Conference: Targeting Epigenetic Readers and Chromatin Remodelers


Day 1 | Day 2 | Download Brochure


Tuesday, September 20

7:00 am Registration Open and Morning Coffee


STRUCTURAL AND MECHANISTIC INSIGHTS INTO DEUBIQUITINASE (DUB) ENZYMES AND INHIBITORS

8:05 Chairperson’s Opening Remarks

Tauseef R. Butt, Ph.D., President and CEO, Progenra, Inc.

8:10 FEATURED PRESENTATION: Mechanism and Specificity of Deubiquitinating Enzyme USP14

Daniel Finley, Ph.D., Professor, Cell Biology, Harvard Medical School

USP14 can suppress degradation of a subset of proteasome substrates, raising the question of USP14 specificity. We studied this using the N-terminus of cyclin B as an in vitro model. Surprisingly, what seems to be the dominant aspect of USP14 specificity is that it will not remove ubiquitin groups from substrates, or will do so only quite slowly, when only a single ubiquitin chain is present on the substrate. Multichain specificity could possibly bias degradation towards single-chain substrates produced by highly processive ubiquitin ligases.

8:50 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. 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 that target other components of the ubiquitin/proteasome system impact DUB activity.

9:20 Chemical Proteomics in the Ubiquitin System – DUBs Take Center Stage

Benedikt Kessler, Ph.D., Professor, Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford

The ubiquitin-specific protease USP7 has been suggested as a potential drug target for a variety of cancers, in particular for Multiple Myeloma, where the treatment with small molecule USP7 inhibitors overcomes resistance to clinical proteasome inhibitors. We have utilized ubiquitin-based active site probes in combination with chemical proteomics workflows to determine the potency and selectivity of deubiquitylating enzyme (DUB) inhibitors in cancer cell culture models.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


DESIGN AND DEVELOPMENT OF NOVEL DUB INHIBITORS

10:35 Ubiquitin Pathway: A New Frontier in Cancer Immunotherapy

Tauseef R. Butt, Ph.D., President and CEO, Progenra, Inc.

Progenra has identified ubiquitin pathway enzymes that control pivot points of immune regulation. Small molecules discovered at Progenra suppress Treg function and unleash anti-tumor Teffector cell responses to melt the tumors in immune competent mice. Detailed mechanisms of the de-ubiquitylase USP7 that are critical for the activity of Tregs will be described. These inhibitors synergistically augment the activity of anti-PD1 antibody, CAR T cell therapy, and cancer vaccines.

11:05 Development and Exploitation of Ubi-Plex™, an Innovative Purpose-Built Drug Discovery Platform for Deubiquitinating Enzymes (DUBs)

Gerald Gavory, Ph.D., Director, Head of Biology, Almac Discovery

Herein, we describe the design and implementation of Ubi-Plex™, a purpose-built drug discovery platform for the identification and optimization of DUB inhibitors. We will highlight the versatility and robustness of Ubi-Plex™ by describing a new case study spanning de novo target identification, focused library screening and hit finding to the development of novel, potent and selective inhibitors ready for lead optimization.

11:35 Discovery of Highly Selective Macrocyclic Inhibitors of DUBs: USP9x as a Case Study

Deborah Dodge, Senior Scientist, Ensemble Therapeutics

We have developed a productive discovery engine based on DNA-encoded libraries of macrocycles that has successfully identi ed novel lead compounds against a number of ubiquitin-speci c proteases. Compounds targeting USP9x exemplify the potency, selectivity, and “drug likeness” potential of this class of inhibitors. Specifcally, these highly selective compounds targeting USP9x exhibit mixed non-competitive and competitive modes of inhibition and possess cytotoxic cellular activity.

11:50 Comprehensive Profiling of DUB Inhibitors

Mark Albertella, D.Phil., Director, Biology, Medivir

As part of our internal drug discovery efforts, we have comprehensively characterized a number of publically disclosed DUB inhibitors in our in-house biochemical and biophysical assays. We outline some of our observations, highlighting the low specificity or high chemical reactivity of a number of these compounds, and the caution that should be exercised when interpreting data obtained using these molecules as pharmacological tools.

12:05 pm Sponsored Presentation (Opportunity Available)

12:35 Session Break

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing


HARNESSING THE UPS FOR TARGETED PROTEIN DEGRADATION

2:05 Chairperson’s Remarks

Gerald Gavory, Ph.D., Director, Head of Biology, Almac Discovery

2:15 KEYNOTE PRESENTATION: PROTACS: INDUCED PROTEIN DEGRADATION AS A THERAPEUTIC STRATEGY

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

The current “inhibitor-/binder-based” paradigm of pharmaceutical control has inherent limitations. Based on an “event-driven” paradigm, this approach offers a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This is achieved via recruitment of target proteins to the cellular quality control machinery using PROTACs (Proteolysis Targeting Chimeras) that can achieve “degradation concentrations” (DC50 values) in the picomolar range.

2:45 Targeted Protein Degradation by Small Molecules

Alessio Ciulli, Ph.D., Associate 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.

3:15 Sponsored Presentation (Opportunity Available)

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:25 A New Paradigm in Drug Action: Differentiated Gain of Function among IMiD Structural Analogues Binding the E3 Ubiquitin Ligase, CRL4CRBN

Brian Cathers, Ph.D., Executive Director, Co-Leader & Head, Drug Discovery, Protein Homeostasis Thematic Center of Excellence, Celgene

Solution of the ligand bound CRBN target complex provides a rationale for distinguishing “gain of function” targeting of key substrates, including the transcription factors aiolos (IKZ3) and ikaros (IKZ1) or the protein kinase CK1alpha. Is it possible to harness the action of a single E3 ligase and direct its actions toward new and different substrates? The presentation will explain distinctions among existing drugs, address guiding concepts applicable to determining new therapeutic applications, and point its therapeutic power.

4:55 PANEL DISCUSSION: Hijacking the UPS for Targeted Protein Degradation

The design of small molecules to hijack the UPS has received significant attention over the past year, with several groups working on various strategies, and biotech spinouts formed. Collectively, this has formed a new paradigm in drug action, and is poised to have broad application and utilization in drug discovery. This panel, comprised of experts at the forefront of this field, will discuss these approaches, applications, and challenges for further development.

Moderator:

John “Jay” Schneekloth Jr., Ph.D., Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH

Panelists:

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

Andrew Phillips, Ph.D., CSO, C4 Therapeutics

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

Brian Cathers, Ph.D., Executive Director, Co-Leader & Head, Drug Discovery, Protein Homeostasis Thematic Center of Excellence, Celgene

5:25 Welcome Reception in the Exhibit Hall with Poster Viewing

6:25 End of Day

Day 1 | Day 2 | Download Brochure


Wednesday, September 21

7:30 am Registration Open and Morning Coffee


DIVERSE STRATEGIES MODULATING THE UPS

8:00 Chairperson’s Opening Remarks

Benedikt Kessler, Ph.D., Professor, Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford

8:10 Discovery of Novel Protein Homeostasis Inhibitors Utilizing FORMA’s Drug Discovery Engine

Stephanos Ioannidis, Ph.D., Director, Medicinal Chemistry, FORMA Therapeutics

Protein homeostasis is important in oncology, neurodegenerative and other medical disorders involving a network of pathways controlling the biogenesis, folding, transport and degradation of proteins. Using FORMA’s innovative chemical libraries approach has led to the discovery of novel protein homeostasis inhibitors which allowed the understanding of pathways and targets associated with excessive protein degradation. The discovery of novel protein homeostasis inhibitors provides the potential for widespread clinical applications.

8:40 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.

9:10 Targeting the Proteasome for Cancer Chemotherapy

Lawrence R. Dick, Ph.D., Scientific Fellow, Takeda Oncology

The proteasome inhibitor VELCADE® (bortezomib) was first approved in 2003 for the treatment of relapsed or refractory multiple myeloma, a cancer of plasma cells in bone marrow. Currently, VELCADE® is indicated for frontline therapy in patients with that disease. This success has engendered great interest in the discovery of new proteasome inhibitors as well as the discovery of drugs that would target other components of the ubiquitin proteasome system. Takeda Oncology’s drug discovery efforts in this area include our recently approved NINLARO®.

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


TARGETING THE PPIs OF E3 LIGASES

10:25 UbFluor: A Novel Tool for HTS and FBDD Screening to Discover Chemical Probes for HECT and RBR E3 Ubiquitin Ligases

Alexander Statsyuk, Ph.D., Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

We present our work toward the rational and systematic approaches to develop small molecule inhibitors of HECT E3 and RBR E3s ubiquitin ligases. These are single subunit ligases that harbor the catalytic cysteine and form the obligatory HECT E3/RBR E3~Ub thioesters prior to ligation of the ubiquitin onto the lysines of protein substrates. Members of HECT and RBR E3s include Nedd4-1, Nedd4-2, ITCH, Parkin, and E6-AP. We used UbFluor to screen 50,000 compounds against two HECT E3s, and identified promiscuous and selective inhibitors. We also screened 2,000 water soluble fragments at 200 uM against three HECTs using UbFluor probe, and we will be presenting our results.

10:55 Stealing Secrets from the Germline: Alterations of Tumor Metabolism by a Testis-Specific Ubiquitin Ligase Hijacked in Cancer

Ryan Potts, Ph.D., Associate Member, Faculty, Cell & Molecular Biology, St. Jude Children’s Research Hospital

AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase.

11:25 Enjoy Lunch on Your Own



2:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:20 End of Conference



Day 1 | Day 2 | Download Brochure

Japan-Flag Korea-Flag China-Simplified-Flag China-Traditional-Flag  

Final Agenda Now Available

Final Agenda Now Available


 PREMIER SPONSOR

Cellecta

Arrow DownCONFERENCE-AT-A-GLANCE

Arrow DownDOWNLOAD 2016 BROCHURE

Arrow OverSHORT COURSES

Arrow OverVIEW ALL SPONSORS

Arrow OverVIEW MEDIA PARTNERS


SPONSORSHIPS & EXHIBITS

The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:

Jon Stroup
Sr. Business Development Manager
781-972-5483
jstroup@healthtech.com

 

Sponsorship-vid

DOT-Vid-recap 

IPR-Special-Report-Packages  

SEPTEMBER 19 SYMPOSIA:

Next-Generation Histone Deacetylase Inhibitors

Strategies for Tackling Rare Genetic Diseases

Understanding CRISPR: Mechanisms and Applications

Autoimmunity – Small Molecule Approaches

NK Cell-Based Cancer Immunotherapy

CONFERENCES

SEPTEMBER 20-21

Targeting Histone Methyltransferases and Demethylases

Targeting the Ubiquitin Proteasome System

Targeting the Microbiome
– Part 1

GPCR-Based Drug Discovery - Part 1

Advances in Gene Editing and Gene Silencing – Part 1

Gene Therapy Breakthroughs

Antibodies Against Membrane Protein Targets – Part 1

Targeting Cardio-Metabolic Diseases

Targeting Ocular Disorders

SEPTEMBER 21-22

Targeting Epigenetic Readers and Chromatin Remodelers

Kinase Inhibitor Discovery

Targeting the Microbiome
– Part 2

GPCR-Based Drug Discovery - Part 2

Advances in Gene Editing and Gene Silencing – Part 2

Translating Cancer Genomics

Antibodies Against Membrane Protein Targets – Part 2

Metabolomics in Drug Discovery

TRAINING SEMINAR: Data Visualization

SHORT COURSES*

Monday, September 19
8:00 - 11:00 am

(SC1) Immunology Basics for Chemists

(SC2) Designing Peptide Therapeutics for Specific PPIs

(SC3) Phenotypic Screening and Chemical Probe Development

(SC4) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 1

Monday, September 19
2:00 - 3:00 pm

(SC5) GPCR Structure-Based Drug Discovery

(SC6) RNA as a Small Molecule Drug Target

(SC7) Using IP Landscape Studies to Improve Your Confidence

(SC8) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 2

Monday, September 19
3:30 - 6:30 pm

(SC9) Targeting of GPCRs with Monoclonal Antibodies

(SC10) Introduction to Targeted Covalent Inhibitors

(SC11) Contact Lens Drug Delivery Systems

(SC12) Introduction to Gene Editing

Monday, September 19
7:00 - 9:30 pm

(SC13) Convergence of Immunotherapy and Epigenetics for Cancer Treatment

Wednesday, September 21
7:00 - 9:30 pm

(SC14) Cancer Metabolism: Pathways, Targets and Clinical Updates

(SC15) Introduction to Allosteric Modulators and Biased Ligands of GPCRs

(SC16) Functional Screening Strategies Using CRISPR and RNAi

(SC17) Challenges and Opportunities in DNA Methyl Transferase (DNMT) Inhibitors as Therapeutics