Day One

Wednesday 17 March

Day Two

Thursday 18 March

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

  • Alessio Ciulli Professor of Chemical Structural Biology, University of Dundee

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

  • Brenda Schulman Director of Molecular Machines and Signaling & Acting Executive Director, Max Planck Institute of Biochemistry

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

  • Georg Winter Principal Investigator, CeMM Research Centre for Molecular Medicine

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

  • Brenda Schulman Director of Molecular Machines and Signaling & Acting Executive Director, Max Planck Institute of Biochemistry
  • Georg Winter Principal Investigator, CeMM Research Centre for Molecular Medicine

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

  • Ivan Dikic Director of Institute of Biochemistry II, Goethe University Frankfurt

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

  • Ivan Dikic Director of Institute of Biochemistry II, Goethe University Frankfurt
  • Dengfeng Gou Executive Director, HitGen

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 Characterization from Bivalent to Trivalent PROTACs

Synopsis

  • Quantitative degradation analysis and determination of efficacy window
  • Cellular analysis of ternary complex formation including induced conformational change, stoichiometry of binding, and rate of formation
  • Analysis of PROTAC permeability and residence time of target binding within the ternary complex

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

  • Simon Bailey Executive Vice President & Head of Drug Discovery, Plexium

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

  • Terry Rabbitts Professor of Molecular Immunology , The Institute of Cancer Research

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

5:10 pm Discussion/Q&A

  • Simon Bailey Executive Vice President & Head of Drug Discovery, Plexium
  • Terry Rabbitts Professor of Molecular Immunology , The Institute of Cancer Research

5:30 pm Chair’s Closing Remarks & End of Day One

See Agenda Day Two