Autophagy and the ubiquitin-proteasome system (UPS) are the two major pathways responsible for protein degradation and maintenance of cellular homeostasis. They consist of well-controlled, selective mechanisms for intracellular protein degradation and turnover. New understanding of the role and molecular mechanisms involved in the dysregulation of autophagy and ubiquitin pathways has revealed its underlying role in cancer, CNS, immunology and other diseases. However, the diversity of substrates and the multi-step processes involved, make it difficult to target these pathways for therapeutic intervention. In recent years, the development of high-quality chemical probes, small molecule modulators, assays and screening platforms have helped identify novel autophagy and ubiquitin targets for drug discovery. Cambridge Healthtech Institute’s conference on Emerging Ubiquitin and Autophagy Targets will bring together a diverse group of chemists and biologists to discuss the promise and challenges in this area of research. This conference will be followed by one that focuses exclusively on targeted protein degradation using proteolysis-targeting chimeric molecules (PROTACs) and other molecular entities for hijacking the ubiquitin system.
Day 1 | Day 2
Monday, September 16
1:00 pm Pre-Conference Short Course Registration
Click here for details on short courses offered.
Tuesday, September 17
7:00 am Registration Open and Morning Coffee
Probing PPI & Protein Degradation
8:00 Organizer's Welcome Remarks
8:05 Chairperson’s Opening Remarks
Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute
8:10 New Technologies to Discover E3 Ligase Inhibitors, Activators, Hijackers
Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston
Two major principles of targeting the ubiquitin system have emerged: direct targeting of the enzymes that control protein ubiquitination and hijacking E3 ligases to induce protein degradation. In this lecture, I will outline the discovery of novel probes UbFluor and cross-linking reagents to discover small molecule inhibitors/activators and hijackers for RBR/HECT E3 ligases. I will then show how UbFluor technology can be used to discover nanomolar inhibitors of HECT E3 ligases.
8:40 Drugging the Fbw7 E3 Ligase with a Combined Computational and Fragment-Based Approach
Carles Galdeano, PhD, Serra Hunter Professor, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona
We have developed a multidisciplinary computational and biophysical approach to identify ligands that target E3 ligases, and specifically the Fbw7 E3 ligase. Fbw7 is one of the most commonly deregulated UPS protein in human cancers, which targets some key human onco-proteins including cyclin-E, MYC, Notch and Junk. So far, no potent small molecule directly targeting the Fbw7 complex has been reported. Our approach has allowed us to identify ligands able to bind at the low micromolar level to the Fbw7 protein. Work is on-going to elucidate the binding mode and the potential MOA of these ligands.
9:10 ULK3 Kinase as a Key Regulator of Cancer Associated Fibroblast Conversion
Sandro Goruppi, PhD, Instructor in Dermatology, Harvard Medical School, Cutaneous Biology Research Center, Massachusetts General Hospital
The connection between pathways and the role of microenvironment metabolic alterations in cancer associated fibroblasts (CAFs) activation is unknown. CSL/RBPJ suppress gene expression program(s) leading to CAF activation. GLI signaling also contributes to CAF conversion. I will report on a degradative autophagy mechanism targeting CSL and leading to CAF activation. Then I will outline the identification and targeting of ULK3 kinase, which links CSL and GLI signaling and represent a tool for stroma-focused anti-cancer intervention.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25 Analysis of Mammalian ER-Associated Degradation Using Genome-Wide CRISPR Screens
Dara E. Leto, PhD, Basic Life Research Scientist, Departments of Biology, Genetics, Chemical and Systems Biology and Program in Chemistry, Engineering and Medicine for Human Health, Stanford University
Only a handful of ubiquitin-proteasome system (UPS) components have been linked to the recognition and degradation of specific protein quality control substrates. To identify genes required for the destruction of distinct clients of the ER-associated degradation (ERAD) system, we developed a screening approach that combines genome-wide CRISPR-Cas9-mediated gene deletions and a phenotypic selection based on protein turnover kinetics. Our findings show that forward genetic analysis can be used to discover new biochemical pathways in protein quality control.
10:55 Engineering Protein-Protein Interactions to Probe and Rewire Ubiquitin Signaling
Wei Zhang, PhD, Assistant Professor, Molecular and Cellular Biology, University of Guelph
Advances of genomic technologies accelerated the identification of signal transduction cascades essential for initiation and progression of human diseases. In particular, protein-protein interactions in ubiquitin signaling are found to play critical roles in eliciting numerous mis-regulated biological functions. We employ structure-based combinatorial protein design and engineering strategies to develop potent and selective modulators to probe the ubiquitin signaling pathways with unprecedented precision for underlying molecular mechanisms and potential therapeutics.
11:25 Structures of the Substrate-Engaged Proteasome Reveal the Mechanism of Translocation and Activation
Andres Hernandez de la Peña, PhD, Postdoctoral Fellow, The Scripps Research Institute
As the primary eukaryotic proteolytic machine, the 26S proteasome is responsible for ubiquitin-mediated degradation of misfolded, damaged, or obsolete proteins. We determined several structures of the proteasome as it actively translocated substrate. These structures reveal the mechano-chemical coupling of ATP hydrolysis to substrate translocation and gate opening. Additionally, these structures reveal a co-translocational deubiquitination mechanism that positions ubiquitin and the isopeptide scissile bond in the Rpn11 deubiquitinase.
11:55 Presentation to be Announced
12:25 pm Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
Developing Small Molecule Ubiquitin-Mediated Degradation
1:50 Chairperson’s Remarks
Yue Xiong, PhD, William R. Kenan Professor of the Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen
1:55 SMARCA2/4 Degraders for Cancer Therapy
Murali Ramachandra, PhD, CSO, Aurigene Discovery Technologies Limited
SMARCA2 and SMARCA4 are ATPases in the SWI/SNF complexes, which function in regulating transcription, DNA replication and repair. SMARCA4 is mutated in a number of cancers, which are dependent on functional SMARCA2. SMARCA4 is also highly expressed without mutation in certain other tumor types, where overexpression contributes to proliferation and survival. In view of these findings, our efforts in developing novel bi-functional molecules inducing proteasome-mediated degradation of SMARCA2/4 for the treatment of cancers will be presented.
2:25 Ubiquitin-Mediated Small Molecule Induced Target Elimination in Cancer
Yue Xiong, PhD, William R. Kenan Professor of the Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen
Development of small molecules to target ubiquitin-dependent degradation of disease-linked proteins represents a promising opportunity for the drug discovery. Multiple such small molecules have been developed based on different E3 ubiquitin ligases. I will discuss the catalytic mechanism, assembly and regulation of cullin-RING E3 ubiquitin ligases (CRLs). I will also present our efforts in developing novel degraders targeting different human cancer protein. Finally, I will share some thoughts on the development of novel E3 ligands.
2:55 Sponsored Presentation (Opportunity Available)
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
NOVEL APPROACHES FOR PROTEIN DEGRADATION
4:05 New Ubiquitin Ligases and Novel PROTAC Approaches
Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.
Ligases that reside primarily in the nucleus are not suited to cytosolic targets, for example, while membrane-associated ligases are required to target GPCRs and other membrane associated targets. Novel E3 ligases and ligands would thus expand the therapeutic potential of PROTACs and provide new IP. I will present data on PROTACs that hijack novel ubiquitin ligases to ubiquitylate targets affecting immune oncology and anti-inflammatory cascades. Degradative versus non-degradative ubiquitylation and relationships between the type of ubiquitylation and PROTAC-targeted function will be discussed.
4:35 Broad-Spectrum Proteome Editing with an Engineered Bacterial Ubiquitin Ligase Mimic
Matthew DeLisa, PhD, William L. Lewis Professor of Engineering, Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University
Ubiquibodies are comprised of a synthetic binding protein fused to an E3 ubiquitin ligase, thus enabling post-translational ubiquitination and degradation of a target protein independent of its function. Here, we have designed a panel of new ubiquibodies based on E3 ubiquitin ligase mimic from bacterial pathogens that enable selective and customizable removal of proteins of interest. Delivery of synthetic mRNA encoding ubiquibodies caused efficient target depletion in cultured mammalian cells as well as in transgenic mice. Overall, our results suggest that engineered ubiquibodies are a highly modular proteome editing technology with the potential for pharmacologically modulating disease-causing proteins.
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. Visit the conference website for discussion topics and moderators.
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
7:10 Close of Day
Day 1 | Day 2
Wednesday, September 18
7:30 am Registration Open and Morning Coffee
Emerging Ubiquitin Targets & Modulators
8:00 Chairperson’s Remarks
Mary Matyskiela, PhD, Principal Scientist, Structural and Chemical Biology, Celgene
8:05 Potent Small Molecule Parkin Activators for Treating Neurodegenerative Diseases
Suresh Kumar, PhD, Senior Director R&D, Progenra, Inc.
Parkin, an ubiquitin E3 ligase, is a critical regulator of mitochondrial dynamics and a protector of neuronal health. Inactivating mutations in both Parkin and PINK1 are found in Parkinson’s disease patients. Using the UbiProTM HTS platform we have discovered novel small molecule Parkin activators. Parkin activators promote degradation of mitochondrial and cytosolic Parkin substrates in human neurons. Development of these Parkin activators offers potentially viable therapeutic options to treat Parkinson’s and other neurodegenerative diseases.
8:35 A Neurodevelopmental Disorder Caused by USP7 Haploinsufficiency
Ryan Potts, PhD, Associate Member, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
USP7 is a prominent deubiquitinating enzyme that has a multitude of cellular functions. Most notably its role in regulation of p53 has garnered much attention. This has resulted in tremendous interest in development of USP7 inhibitors for cancer treatment. Here, I will discuss progress in understanding how mutation or deletion of a single copy of USP7 leads to a neurodevelopmental disorder. The implications of these findings in drug development will be discussed.
9:05 Sponsored Presentation (Opportunity Available)
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 Use of Tip60 PROTACs in Cereblon-Knockin Mice
Wayne W. Hancock, MD, PhD, Professor, Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania
Finding new ways to target histone acetyltransferases such as Tip60 is important for advances in immuno-oncology, and the PROTAC approach makes this possible. However, mice have a single amino acid substitution that blocks efficient iMID-dependent recruitment of the E3-ligase, Cereblon, limiting experimental studies. We report use of Tip60 PROTACs in WT vs. Cereblon-knock-in mice in which PROTAC-dependent recruitment is now rendered active, allowing use of murine models for testing of this and other PROTAC molecules.
10:50 FEATURED PRESENTATION: Advancing Targeted Protein Degradation for CNS Proteinopathies
Stephen. J. Haggarty, PhD, Associate Professor, Department of Neurology, Harvard Medical School; Associate in Neuroscience and Director, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital
Exploiting the control of protein proximity to catalyze targeted protein degradation provides a potentially powerful therapeutic strategy. Recent advances enabling the generation of patient-derived, ex vivo models of central nervous system (CNS) proteinopathies and the development of bifunctional molecules capable of selectively targeting pathological protein conformations now allow this strategy to be applied to the context of neurodegeneration. Here we will summarize recent findings focused on targeted degradation of tau, a protein implicated in multiple forms of dementia.
11:20 Enjoy Lunch on Your Own
11:20 Conference Registration for Programs 1B-7B
PLENARY KEYNOTE PROGRAM
Click here for full abstracts.
12:20 pm Event Chairperson’s Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction
12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University
1:20 PROTACs: Past, Present, and Future
Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing
2:45 Close of Emerging Ubiquitin and Autophagy Targets Conference
Please click here to continue to the agenda for PROTACs and Targeted Protein Degradation
* The program is subject to change without notice, due to unforeseen reason.