The ubiquitin-proteasome system (UPS) is a well-controlled, selective mechanism for intracellular protein degradation and turnover, and it acts as a key regulator in cancer, CNS and other diseases. However, the multi-step processes involved and the diversity
of substrates make it difficult to target the UPS. Proteolysis-targeting chimeric molecules (PROTACs) are a group of engineered hetero-bifunctional chemical entities that bind to the target and ligase to mediate ubiquitination and subsequent protein
degradation. Like PROTACs, other chemical entities and molecular glues, using varied mechanisms-of-action, are being developed to trigger targeted protein degradation. These approaches have a lot of potential in seeking out previously “undruggable”
protein targets for applications in drug discovery and for developing new therapeutic modalities. However, some challenges do exist in terms of stability, biodistribution and penetration of these molecules in vivo. Cambridge Healthtech Institute’s
conference on PROTACs and Targeted Protein Degradation will bring together a diverse group of chemists and biologists to discuss the prospects, as well as, the challenges underlying strategies for targeted protein degradation. This will be preceded
by a conference that discusses emerging ubiquitin and autophagy targets for therapeutic intervention.
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Final Agenda
Wednesday, September 18
11:20 am Conference Registration Open (America Foyer)
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
Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd
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 (America Ballroom)
2:45 Organizer's Welcome Remarks
2:50 Chairperson’s Opening Remarks
Peter Dragovich, PhD, Staff Scientist, Discovery Chemistry, Genentech
2:55 Translating Cellular Degradation Insights to in vivo Models
Stewart Fisher, PhD, CSO, C4 Therapeutics
Targeted protein degradation, through the use of heterobifunctional degraders that act as catalytic activators for an E3 ligase and target protein, has the potential to transform drug discovery. This talk will discuss the application of an enzymology
framework to characterize cellular degradation data and the extension of these insights to pharmacodynamic modeling and predictions.
3:25 FEATURED PRESENTATION: Targeting the Undruggables Using PROTACs
Shaomeng Wang, PhD, Warner-Lambert/Parke-Davis Professor of Medicine, Pharmacology and Medicinal Chemistry; Co-Director, Molecular Therapeutics Program and Director, Cancer Drug Discovery Program, University of Michigan
I will present our recent efforts to design potent, selective and highly efficacious degraders to target STAT3 (signal transducers and activators of transcription 3), a classical undruggable target by small molecules. In vitro and in vivo data demonstrate that our most promising STAT3 degrader is highly potent and effective in inducing degradation of the STAT3 protein and demonstrates absolute selectivity over other STAT members. It achieves
complete and long-lasting tumor regression in multiple xenograft models in mice at well tolerated dose-schedules.
3:55 Novel Approaches to PROTAC Drug Discovery
Dahmane Ouazia, PhD, Business Development Manager, LifeSensors, Inc.
Karteek Kadimisetty, PhD, Assistant Director, Research & Development, LifeSensors, Inc.
Current methods for PROTAC drug discovery are inefficient and full of artifacts. We developed a plate-based methodology for rapid screening of PROTAC-mediated protein ubiquitination, a true measure of PROTAC drug effect. This method is faster, more reproducible
and requires less starting material than already used Western blotting and reporter assays.
4:10 Sponsored Presentation (Opportunity Available)
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Pharmacokinetics Related Challenges of PROTACs
Upendra Dahal, PhD, Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.
PROTACs are bifunctional molecules, designed to bind with target protein and E3 ligase to degrade protein of interest by hijacking cell’s ubiquitin proteasome system. Several challenges remain in designing optimal PROTACs that has good PK properties
to show efficacy in vivo. For example, PROTACs have high MW (beyond rule of 5), low permeability and low oral bioavailability. This presentation will focus on pharmacokinetics related challenges of PROTACs to share/discuss/improve
PK properties of PROTACs.
5:30 Targeted Protein Degradation Enters the Clinic: Insights From ARV-110 and Other PROTAC® Degraders
Miklos Bekes, PhD, Research
Investigator, Platform Biology, Arvinas, Inc.
The orally bioavailable, androgen receptor-targeted PROTAC protein degrader ARV-110 entered Phase I clinical trials for metastatic, castration-resistant prostate cancer in 1Q19; and is followed by a planned 3Q19 clinical trial initiation for the orally
bioavailable, estrogen receptor-targeted PROTAC® protein degrader ARV-471 for ER+ locally advanced or metastatic breast cancer. I will present learnings from these programs. Additionally, I will discuss results for tau-targeted PROTAC protein
degraders for potential application in Alzheimer’s disease and other tauopathies.
6:00 Antibody-Mediated Delivery of Protein Degraders
Peter Dragovich, PhD, Staff Scientist, Discovery Chemistry, Genentech
Chimeric Chemical Inducers of DEgradation (CIDEs) which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds
that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of CIDEs to monoclonal antibodies
using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these agents.
6:30 Dinner Short Course Registration (America Foyer)
Click here for details on short courses offered.
9:30 Close of Day
Thursday, September 19
7:00 am Registration Open (America Foyer)
Essex Ballroom
7:30 Interactive Breakfast Breakout Discussion Groups - View All Breakouts
Grab a cup of coffee and 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.
Designing and Optimizing Chemistry and Drug-Like Properties of Protein Degraders
Moderators: Ye Che, PhD, Head of Computational Design, Discovery Sciences, Pfizer, Inc.
Michael Plewe, PhD, Vice President, Medicinal Chemistry, Cullgen, Inc.
- Design of protein degraders, linkers
- Kinetics of binding and degradation
- Ternary complex formation
Novel Strategies for Protein Degradation
Moderator: Stewart Fisher, PhD, CSO, C4 Therapeutics
- Applying enzymology concepts to the optimization of targeted protein degraders
- Developing biochemical and cell-based assays for studying protein degradation
- Protein degradation beyond bi-functional degraders
Overcoming Translation Challenges
Moderators: Peter Dragovich, PhD, Staff Scientist, Discovery Chemistry, Genentech
Shaomeng Wang, PhD, Warner-Lambert/Parke-Davis Professor of Medicine, Pharmacology and Medicinal Chemistry; Co-Director, Molecular Therapeutics Program and Director, Cancer Drug Discovery Program, University of Michigan
- Pursuing previously undruggable protein targets
- Exploring use of PROTACs and other protein degraders for oncology
- Issues surrounding PK/PD, biotransformation, in vivo pharmacology, and delivery
8:30 Transition to Sessions
8:40 Chairperson’s Remarks
Ye Che, PhD, Head of Computational Design, Discovery Sciences, Pfizer, Inc.
8:45 Targeted Protein Degradation for Treatment of Cancer
Michael Plewe, PhD, Vice President, Medicinal Chemistry, Cullgen, Inc.
Targeted protein degradation using bifunctional molecules to remove specific proteins by hijacking the ubiquitin proteasome system has emerged as a novel drug discovery approach. Several challenges remain in designing optimal degraders that also show
efficacy in vivo. We will present case studies from our ongoing efforts in the design and biological evaluation of novel degraders for selected oncology targets that display in vivo activity in mouse models.
9:15 NEW: Targeted Protein Degradation: A Rational & Scalable Drug Discovery Approach
Nello Mainolfi, PhD, Founder and CSO, Kymera Therapeutics, Inc.
Targeted protein degradation combines the power of eliminating a disease-causing protein with the advantages of small molecule circulation in the body. Kymera is pioneering and advancing this technology by designing novel heterobifunctional molecules
that engage the target protein and the E3 ligases to direct the target protein to be selectively degraded by the ubiquitin proteasome system. We have shown promising pre-clinical data packages with IRAK4 and STAT3, key nodes in innate immunity and
cancer, and continue to build a robust pipeline supported by our integrated degradation platform. This presentation will cover an overview of Kymera’s holistic drug discovery design and development.
9:45 Establishing a Platform for High-Throughput Identification and Profiling of Target Degraders
James Robinson, PhD, Team Leader, Discovery Sciences, AstraZeneca
Target degradation can provide additional benefits over target inhibition and can in some cases enable targets that were previously considered intractable. Here I present our approaches to identify degraders of two high profile drug targets. In the first
case we deployed a suite of high throughput plate-based assays to enable profiling and optimisation of a series of PROTACs. In the second case we performed a high throughput screen to identify novel small molecule degraders.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (America Ballroom)
10:55 Computational Design of PROTACs
Ye Che, PhD,
Head of Computational Design, Discovery Sciences, Pfizer, Inc.
Orthosteric and allosteric modulators of enzyme function or receptor signaling are well-established mechanisms of drug action. Drugs that promote novel protein-protein interactions and induce protein degradation promise to dramatically expand opportunities
for therapeutic intervention. This approach is more difficult for rational design due to the extensive contact surfaces that must be perturbed antagonistically. Here, I will highlight recent applications of computational methods in the design and
optimization of targeted protein degraders.
11:25 Structure-Based Design of Degraders
Radosław Nowak, PhD, Scientist, Laboratory of Dr. Eric Fischer, Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School
Small molecule degraders have shown considerable promise as a new pharmacological modality. With the mounting structural information on degrader mediated ligase-substrate interactions we are beginning to understand the rationale for target recruitment
and selectivity. This presentation will describe a recently developed framework for use of computational tools, such as protein-protein docking, for accelerating degrader design.
11:55 In Silico Modeling of PROTAC-Mediated Ternary Complexes for Predicting Protein Degradation
Michael Drummond, PhD, Scientific Applications Manager, Chemical Computing Group
Successful development of Proteolysis-Targeting Chimeras (PROTACs) hinges upon the ability to rationally modify and design new PROTACs. We have recently developed a suite of computational tools for generating ensembles of PROTAC-mediated ternary complexes.
Furthermore, we propose metrics based on available experimental knowledge to identify the structures within the larger ensemble that are likely to degrade. We demonstrate the utility of our methods in a number of scenarios, including across different
targets and PROTAC molecules.
12:25 pm Session Break
12:35 Enjoy Lunch on Your Own
1:25 Refreshment Break in the Exhibit Hall with Poster Viewing
2:05 Chairperson’s Remarks
Nello Mainolfi, PhD, Founder and CSO, Kymera Therapeutics, Inc.
2:10 KEYNOTE PRESENTATION AND DISCUSSION: Targeting Kinases for Degradation- Challenges and Opportunities
Nathanael S. Gray, PhD, Professor of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein
targets. In this talks I will discuss our efforts to develop chemoproteomic strategies to identify degradable kinases. Methods to characterize small molecule kinase degraders will also be discussed.
3:10 E3 Ubiquitin Ligases for PROTACs Discovery
Matthieu Schapira, PhD, Principal Investigator, Structural Genomics Consortium and Associate Professor, Pharmacology & Toxicology, University of Toronto
To be active, a PROTAC must induce the formation of a productive complex between a target of interest and a structurally and functionally compatible E3 ubiquitin ligase. Considering that less than ten E3 ligases out of over 600 in the human proteome are
exploited by current PROTACs, extending the repertoire of lig-ands to E3 ligases with a variety of structural properties as well as diverse temporal and spatial expression profiles should considerably expand potential applications of
PROTACs for chemical biology, and broaden the horizon for future drug discovery efforts. I will review the classification, ubiquitin-proteasome system association, tissue expression profile and druggability of human E3 ligases.
3:40 Close of Conference
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