8:30 am Online Registration & Networking Coffee
8:55 am Chair’s Opening Remarks
KEYNOTE Session: Discovering the Full Potential of Protein Degrader Approaches to Open Up Therapeutic Opportunity
9:00 am Bringing Proteins Together with Small-Molecule Degraders
Synopsis
- Small molecules that recruit proteins to E3 ubiquitin ligases for targeted protein
degradation are a novel modality of chemical intervention for biology and
medicine - Highlighting fundamental structural, biophysical and mechanistic insights into
degraders’ ternary complexes, showing that induced protein–protein interaction is
a general feature of their molecular recognition - Modularity of design, from monovalent glues to bifunctional molecules, as well
as our recent multivalent degraders, provides fertile ground and fresh chemical
space to untap new biology and pursue compelling therapeutic paradigms
9:20 am Ubiquitylation by Cullin-RING E3 Ligases – How Targeted Protein Degradation is Possible
Synopsis
- Overview of cullin-RING E3 structure
- Structural basis for cullin-RING E3 ubiquitylation
- Implications for targeted protein degradation
9:40 am Discovery of Molecular Glue Degraders via Phenotypic Chemical Screens
Synopsis
- Coupling genome-scale CRISPR screens with degrader treatment identifies a comprehensive network of cellular effectors required for efficient TPD
- Development of isogenic, hyponeddylated cell line models based on this effector network empowered differential chemical screening to identify novel and molecular glue degraders
- Multi-omics target identification led us to identify novel degraders of Cyclin K that operate via a unique mechanism that is independent of a dedicated substrate receptor
10:00 am Discussion/Q&A
10:20 am Virtual Speed Networking
Utilising Next-Generation Approaches to Advance Novel Target Identification
11:20 am Targeting Protein Aggregates and Damaged Organelles via Autophagy and Lysosome Pathways
Synopsis
- Explore chemical approaches to induced selective autophagy in removing protein aggregates and non-functional organelles
- Better understand the cross talk between ubiquitin-proteasome and autophagy pathways
- Investigate the spectrum of E3 ligases to be used in PROTAC methods
11:40 am Enabling DNA Encoded Libraries as a High Content Discovery Tool for Protein Degradation Molecules
Synopsis
- DNA encoded library (DEL) is an optimal discovery tool for protein degradation molecules because both techniques share the same key principles such as affinity binding selection and combination of structural blocks
- Our pilot study designed an E3 tri-conjugate DEL library with more than 390K compounds including BRD4 binder, 16 linkers and thalidomide. We captured novel dBET1 like compounds validated with BRD4 protein degradation using dual binder DEL selection method developed in house
- This DEL protein degradation system also generates other information such as binding affinity that helps predict protein degradation efficacy of compounds, and the system can be extended to other targets and E3 ligases of interest
12:10 pm Discussion/Q&A
12:30 pm Lunch Break
Diversifying TPD Strategies by Uncovering Novel E3 Ligases
1:30 pm A Buchwald-Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3-Ligase PROTACs
Synopsis
- CRBN binders have some of the best physicochemical properties to make PROTACs with that lie within the extended rule of five properties
- Existing methods to synthesise lenalidomide-like CRBN binders that vary the group to the isoindolinone require inserting chemical diversity at the first synthetic step
- We developed a robust Buchwald-Hartwig methodology to introduce a wide range of amines suitable for elaboration into full PROTACs
1:50 pm Affinity-Directed PROtein Missile (AdPROM) System: Deploying Protein Missiles for Targeted Proteolysis of Endogenous Intracellular Proteins
Synopsis
- By using E3 ligases coupled to small polypeptide binders of POIs, the AdPROM system can efficiently target POI proteolysis in cells
- We have successfully used the AdPROM system to target the rapid degradation of many endogenous proteins, including SHP2, ASC and RAS isoforms and misfolded proteins in neurodegenerative disorders
- The efficiency and versatility of the AdPROM system allows to quickly identify degradation-capable E3 ligases in different cellular systems and rapidly informs whether targeted POI degradation confers suitable drugging strategy
2:10 pm Expanding the E3 Space for PROTAC Development
Synopsis
- E3 crystal structures and ligand screening show tractability for developing small molecule binders for a large range of E3s
- Developing binders for more E3s should increase the repertoire of substrates amenable to PROTAC-dependent degradation
- Tissue-selective E3 expression provides opportunity for tissue selective PROTAC
2:30 pm Cellular Mechanistic Profiling of Degradation Compounds
Synopsis
- Several case studies to understand PROTAC mechanism of action in different systems
- Correlation of real-time kinetic degradation profiles to ternary complex formation and ubiquitination
- Cell-based assay strategies for rank ordering compound potency and efficacy
3:00 pm Discussion/Q&A
3:30 pm Virtual Networking & Poster Session
Exploring Autophagy, Screening-Based & Antibody Fragment Approaches to Induce Protein Degradation
4:30 pm Discovery of New Molecular Glues in Immune-Oncology & CNS Diseases
Synopsis
- Pros and cons of ‘molecular glues’ vs PROTACS
- Discovery of new molecular glues using novel ultra-high throughput screening and chemistry platforms
- Application to drug discovery projects in I/O and CNS diseases
4:50 pm Selective Protein Degradation in Cancer using Engineered Intracellular Antibodies or DARPIns
Synopsis
- Intracellular antibodies and DARPins are biologics that can be fused with E3 ligases by protein engineering
- Addition of these E3 ligase warheads elicits protein degradation when the biologics engage with their target proteins
- KRAS-selective biologics with fused to E3 ligases cause cancers with KRAS mutation to undergo apoptosis
- This is a general strategy for biologic-induced target protein degradation in cells