Morning Plenary Session
8:00 am Morning Networking Coffee
8:45 am Chair’s Opening Remarks
Leveraging the Lessons Learned From the Clinic to Bolster Translation of Next Wave of Novel Degraders
9:00 am Findings from the First-in-Human Phase 1 Trials of NX-2127 and NX-5948, Bruton’s Tyrosine Kinase (BTK) Degraders, in Patients with Relapsed/Refractory B Cell Malignancies
Synopsis
- Observe how the activity demonstrated by the BTK degraders, NX-2127 and NX-5948 in phase 1 clinical trials, provide proof of concept for clinical potential of targeted protein degradation
- Understand that all BTK degraders are not created equally
- Learn how BTK degradation overcomes mutational liabilities associated with BTK inhibitors
9:30 am It’s Degrading…. Or Is It?
Synopsis
- Exploring a recent screening effort against an oncology target
- Uncovering the subsequent implications for target selection, and the type of control experiments required
- Detailing the factors in the targeted degradation of short-lived proteins
10:00 am Panel Discussion: How do we Differentiate Degraders from Inhibitors as a Therapeutic Modality?
Synopsis
- How do we break away from the inhibitor-based ligands like BRAF? Do we need to?
- How are we finding new, exciting targets?
- How do we address the problems with VHL pharmacology such as its larger size?
10:45 am Morning Break & Networking
Track A: Discovery & Early-Stage Development
Novel Platforms & Screening for High Throughput Targets & E3 Hit Finding for PROTACs
11:45 am Panel Discussion: Can Computational Approaches Deliver on the Promise of More Efficient & Accurate Degrader Discovery & Development?
Synopsis
- What is limiting AI/ML from accelerating TPD development?
- “Lots of data is needed” – how much? And how do we get there?
- Can we make the data available more amenable?
- What can computational methods currently deliver?
- What will happen to traditional approaches like docking?
12:15 pm Improving PROTAC Selectivity by a Degron Blocking Strategy
Synopsis
- Harnessing a structural based understanding of where IMiD induced off target degradation derives
- Spotlighting ligand design strategies to block IMiD-like recruitment of neosubstrates to CRBN
- Demonstrating proof of concept in the context of a BRD9 PROTAC degrader with enhanced selectivity
Track B: Preclinical, Translational & Clinical Considerations
Harnessing Best-in-Class Modeling Systems, Unique Modes of Action, & Tissue-Sparing Ligases to Address Selectivity, Safety, & Efficacy Over Inhibition
11:45 am Chemical Biology Approaches for Protein Degradation
Synopsis
- Covalency and covalent ligand discovery in TPD
- Context-dependent TPD
- Chemical probes to enable bifunctional and glue discovery
12:15 pm Improving Pre-Clinical Safety Assessment with Microphysiological Systems
Synopsis
- Outline the context of use of microphysiological systems (MPS) to generate safety and efficacy data for drug development with improved clinical relevance over more traditional 2D cell culture and animal models
- Highlight examples of data generated from these systems that demonstrate the utility of MPS for safety assessment
- Current challenges to the adoption and/or development of MPS in the pharmaceutical industry
12:45 pm Lunch Break & Networking
1:45 pm Bifunctional Degrader Discovery with PROTEINi Screening
Synopsis
- Performing phenotypic screening for protein degraders using PhoreMost’s PROTEINi technology has identified several novel bio-active degron peptides and their corresponding E3 ligases
- Harnessing target-specific screening to allow the development of biological bifunctional protein degrader molecules
- Showcasing how PROTEINi/E3 ligase interaction can be used to inform and accelerate the development of small molecules that interact with E3 ligases and build novel heterobifunctionals
2:15 pm Biophysical Simulations & Machine Learning for the Discovery of Small Molecule Degraders
Synopsis
- Introduction to Sibylla’s computational platform, including an overview of methods for folding simulations and folding intermediates identification
- Describing Sibylla’s ML-based computational tools for the detection of druggable pockets on protein structures
- Outlining Sibylla’s AI-based methods for the identification of hit compounds
2:45 pm GlueE3, A Modelling Platform for True Rational MG Screening
Synopsis
- Modelling is capable of accurately pair ligases with proteins of interest (POI)
- Given a ligase-POI binary complex, glueE3 can rationally (and efficiently) screen for novel MGs
- Using Large Language Models we can learn the protein-protein dialect, revealing intriguing aspects of ligase pairing
1:45 pm Panel Discussion: The Influence of Physicochemical & ADME Properties on Delivering Oral PROTACs
Synopsis
- How useful are ADME properties for design and optimisation of oral PROTACs?
- Opportunities of different analytical and in silico tools to advance drug design
- Challenges faced in synthesis and purification of PROTACs
2:15 pm Exploring Disease Indications Beyond Oncology where TPD is Poised to Deliver Real Value
Synopsis
- Highlighting developments in the immunology and topical application space for degraders
- Pinpointing underserved indications where TPD can deliver benefit unimpeded by existing therapies
2:45 pm Molecular Glues, Better Options Than PROTACs, Parkin Ligase, Parkinson’s Disease & Beyond
Synopsis
- Exploring how parkin ligase plays a critical role in mitophagy and mitobiogenesis. Mutations in parkin ligase leads to early onset of Parkinson’s disease (PD). The dysfunction of parkin ligase is also attributed to late onset of PD
- Discovering molecular glues that bind parkin, activate parkin function, induce mitophagy in neuronal cells and cardiomyocytes
- Unveiling animal model data suggesting that molecular glues are superior to PROTACs, and easily cross blood brain barriers to have efficacy. Role of parkin in PD and muscle function will be described
3:15 pm Afternoon Break & Networking
Unravelling Induced Proximity’s Potential to Degrade
3:45 pm Targeted Protein Degradation to Explore the Potential of Histone Lysine Deacetylases (HDACs) in Inflammation
Synopsis
- Non-selective small molecule inhibitors of Histone lysine deactylases (HDACs) are clinically applied in oncology
- HDACs are enzymes that have catalytic functions but they also play a role in protein-protein interactions
- Application of the PROTAC technology enable targeting the non-enzyme functions of HDACs
4:15 pm Mapping E3 Ligase Binding sites by Photoreactive Fragment Pharmacophores
Synopsis
- Introducing a new screening concept that combines evolutionary optimized fragment pharmacophores with the use of photoaffinity labelling
- Enabling high hit rates against challenging targets and identifying the binding site by mass spectrometry
- Spotlighting how the performance of the approach is demonstrated against a PPI target, a transcription factor and an E3 ligase
4:45 pm Introducing a New Modality in Targeted Protein Degradation: Intramolecular Bivalent Glue (IBGs)
Synopsis
- Exploring mechanistic insights into action of IBGs through bridging protein domains to enhance surface complementarity with E3s
- Using orthogonal genetic screening, biophysical characterisation and structural reconstitution to investigate MOA
- Confirming MOA with measures of ubiquitination and degradation