8:00 am Registration & Networking Coffee

8:50 am Chair’s Opening Remarks

Pioneering Structural & Biophysical Technologies to Drive Forward Targeted Protein Degradation

9:00 am Inducing Protein Degradation with Bifunctional Small Molecules

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

Synopsis

  • Recent years have seen a resurgence of interest in designing bifunctional molecules that serve as bridging agents to bring proteins together
  • Recruitment of target proteins to E3 ubiquitin ligases to induce protein degradation promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention
  • Pioneering structural and biophysical studies of the ternary complexes formed by these molecules highlight that proximity-induced de novo formation of protein–protein interactions is a general feature of their molecular recognition

9:30 am 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

10:00 am Genetic Determinants of Targeted Protein Degradation: Resistance and Beyond

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

Synopsis

  • Coupling genome-scale CRISPR screens with degrader treatment enables a comprehensive network of cellular effectors required for efficient TPD
  • Scalable mutagenic profiling of 50 key effector genes in hundreds of spontaneously resistant clones points to resistance mechanisms of possible clinical relevance
  • Intersecting functional genomics with structural biology allows determination of key interfacial residues driving ternary complex formation

10:30 am Speed Networking & Morning Refreshments

Utilising Next-Generation Approaches to Advance Novel Target Identification

11:30 am Next-generation PROTAC Discovery with a Systematic Screening Engine

Synopsis

  • Small molecule PROTAC development is hampered by a low complexity matrix of E3 recruitment modules, and hindered by a high degree of substrate specificity
  • PhoreMost have developed SITESEEKER, an ultra-high throughput pooled phenotypic screening platform, exploiting high-diversity programmable drug mimetics
  • Systematic application of the SITESEEKER tools to PROTAC discovery has yielded a substantial cache of novel E3 ligase ligands and peptide-based PROTACs which have been deployed to degrade key therapeutic targets

12:00 pm Enabling DNA Encoded Libraries as a High Content Discovery Tool for Protein Degradation Molecules

  • Jin Li Chairman & Chief Executive Officer, HitGen

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

12:30 pm Networking Lunch

Diversifying Druggable Targets & Disease States to Open up TPD Therapeutic Opportunities

1:30 pm Next-Generation Functional Genomics Approaches to Advance Protein Degradation Strategies

Synopsis

  • Understanding how PROTAC molecules and protein degraders work is critical for their clinical success
  • How can we leverage functional genomics and genome-wide arrayed CRISPR screening capability to decipher the mechanism of action of protein degradation molecules
  • Presentation of case studies highlighting the above

2:00 pm Deubiquitylating (DUB) Enzyme Targeting for Treatment of Human Disease

  • Paul Thompson Vice President of Clinical Development, Mission Therapeutics

Synopsis

  • DUBs antagonize action of ubiquitin ligases – inhibiting the inhibitor
  • DUB specificity/localisation informs target/indication selection – USP30 as an example
  • DUB opportunities exist in neurodegenerative disease

2:30 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

3:00 pm Afternoon Refreshments & Poster Session

Exploring Autophagy & Antibody Fragment Approaches to Induce Selective Degradation

4:00 pm Proximity-Induced Drugs 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 the ubiquitin-proteasome system and autophagy pathways
  • Investigate the spectrum of E3 ligases to be used in PROTAC methods

4:30 pm Engineering Intracellular Antibody Fragments for Targeted Protein Degradation

  • Terry Rabbitts Professor of Molecular Immunology, Weatherall Institute of Molecular Medicine; University of Oxford; The Institute of Cancer Research

Synopsis

  • Intracellular antibody fragments can be engineered to carry functional warheads
  • These warheads require engagement of the antibody fragments with their protein target to produce a response
  • Relevant warheads are those that can induce target protein degradation following antibody fragment binding to the target protein in cells

5:00 pm Chair’s Closing Remarks & End of Day One