Conference Day Two
**All times in EDT**
8:30 am Chair’s Opening Remarks
Harnessing Chemical Biology for Discovery & Development of Ubiquitin Ligases with Therapeutic Value
9:00 am Activation of the RING E3 Anaphase-Promoting Complex/ Cyclosome (APC/C)
Synopsis
- Exploring the APC/C as master regulator of the cell cycle
- Discuss the benefits of APC/C ubiquitination activity as tightly regulated and dynamic
- Outline a mechanism to stimulate the APC/C and the implications for other RING E3s and the cell cycle
9:25 am Molecular Mechanisms of Small Molecule-mediated NEDD4 Targeting
Synopsis
- Reviewing the C2-WW-HECT E3s (also named NEDD4 family) as they appear to be promising targets for drug discovery. Their activity is tightly controlled through an auto-inhibitory interaction of C2 with HECT domain that can be released upon phosphorylation
- Exploring how they build K63-specific chains using a sequential addition mechanism and utilize a ubiquitin exosite required for enzyme processivity
- Discussing how we generated small molecules capable of selectively inhibiting NEDD4 polyubiquitylation without affecting its monoubiquitylation activity. These molecules are currently testing towards tumours of neuroendocrine origin
9:50 am Drugging Transcription Factors and Kinases by Preventing E3- Dependent Degradation
Synopsis
• Building on our understanding of the role of aging in disease to discover new therapies
• Leveraging E3 biology to enhance the beneficial effects of therapeutic proteins with short half-lives
• Outlining generian’s two IND programs and how they address previously undruggable validated therapeutic targets, both with an opportunity for clinical proof of mechanism in rare conditions, with expansion into common disorders
10:15 am Live Panel Q&A – Ask the Speakers Your Burning Questions!
10:30 am
Morning Break & Speed Networking
Exploring Rational Design & Future Potential of Harnessing E3 Ligases for Therapeutic Application
11:30 am Targeting the Ubiquitin Ligase Activity of MDM2
Synopsis
- Exploring the inactivation of MDM2’s ubiquitin ligase activity stabilizes p53 but can still limits p53 activity
- Discussing ligase inactive MDM2 mouse restrains p53 activity for normal growth but enhances p53 activity upon stresses
- Sharing insights into targeting the catalytic activity of MDM2
11:55 am What Makes Two Proteins Stick: Dissecting E3’s Contribution to Molecular Glue Action
Synopsis
- Protein-protein interactions can be induced by slight modification of the surface chemistry of the target!
- How can this be routinely triggered by small molecules?
- Or is this likely already an intrinsic property of many drugs?
12:20 pm Accelerate Mass Spectrometry Protein Sample Preparation and Quantification
Synopsis
- Discovery and targeted proteomics
- Options for high throughput profiling
- Custom peptides for therapeutics & vaccine development
12:35 pm Live Panel Q&A – Ask the Speakers Your Burning Questions!
12:50 pm
Lunch Break & Networking
1:50 pm PANEL DISCUSSION: Exploring the Therapeutic Value of Targeting E3 Ubiquitin Ligases
Synopsis
Using advanced techniques, our understanding of E3 ligases complex structure has improved, identifying bindable pockets on E3 ubiquitin ligases. Similarly, innovative screening methods have identified ligase binders. With this, how can we begin thinking about these interactions as a starting point for viable
- Examining the industry standpoint on E3 targeted therapeutics and the overarching strategy to consider targeting E3’s as a viable therapeutic
- What are the next steps to enhance small molecule targeting E3 therapies into the clinic and beyond?
- As tissue-selectivity becomes increasingly important, what are the difficulties of selectively targeting E3’s in tumor cells and tissue types of interest?
- What breakthroughs and milestones on the horizon?
2:50 pm Poster Session – Present, Learn & Collaborate
Synopsis
As the viability of harnessing E3’s for therapeutic application becomes increasingly evident, it is more important than ever to collaborate and learn with your peers as we continue to advance ligase targeted therapies through discovery and development.
Join our dedicated session to share your latest data and have a first look about what your peers are working on!
3:30 pm Structure Based Design of E3 Targeted Protein Degraders
Synopsis
- Discussing the viability and mechanisms of molecular glues
- Outlining optimal structure-based drug design of E3 protein degraders
- How you can leverage the structural insight of E3 ligases for an effective degrader mechanism
3:55 pm CRL E3 Ligases: From Catalytic Mechanisms, Assembly to Targeted Protein Degradation
Synopsis
- Can we target RING-type E3 ligases?
- Why are CRL E3 ligases particularly suitable for targeted protein degradation?
- How can we hijack CRL to target other proteins?
4:20 pm From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9
Synopsis
- Identification and optimization of a Small Molecule Ligand for PCSK9
- Demonstration of binding of that ligand in complex mixtures
- Development of PCSK9 degrader based on that ligand