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 Monitoring Dynamics of Protein Degradation in Living Cells

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

10:30 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

Leveraging Next Generation Tools to Advance Protein Degradation

11:30 am Enabling Therapeutic Degradation of Undruggable Targets

Synopsis

  • DNA-encoded library (DEL) technology is uniquely enabling for development of the next generation of PROTAC therapeutics: DEL can yield ligands with the desired attributes for compelling but undruggable targets
  • DEL is equally powerful at generating adequate ligands for recruiting E3 ligases via PROTACs
  • Generation and characterisation of potent SHP2 PROTACs; comparison with allosteric inhibitors

12:30 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

12:30 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

1:00 pm Networking Lunch

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

2:00 pm Selecting Targets to Harness the Therapeutic Opportunities Afforded by PROTAC-Mediated Protein Degradation

  • John Harling Senior Scientific Director of Medicinal Chemistry, GlaxoSmithKline

Synopsis

  • With a significant proportion of the intracellular proteome likely being amenable to PROTAC-mediated degradation, considerable focus needs to be placed on identifying the best therapeutic opportunities for this technology
  • This presentation will share some experiences at GSK assessing different targets and the consideration of whether a PROTAC approach represented the modality of choice
  • Data will be presented highlighting how factors such as protein synthesis rates, the relationship between the extent of degradation and functional response as well as additional pharmacology that cannot be accessed via an inhibitor can impact this assessment

2:30 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

3:00 pm Harnessing the Cell’s Degradation Machineries Nature’s Way to Manipulate Protein Stability

  • Laura Itzhaki Professor, University of Cambridge; Chief Scientific Officer, PolyProx Therapeutics

Synopsis

  • The common underpinning basis of the cell’s proteostasis network is molecular recognition involving the specific interactions of proteins with one another. The Polyproxin™ platform exploits our understanding of these interactions to harness proteostasis networks and thereby manipulate protein stability and disease outcome
  • The platform comprises libraries of target-engagement modules and degradation-inducing modules in a mix-and-match format to identify the best
    combination for effective knockdown of the target
  • The platform can thereby be directed to diverse targets and disease states by coopting the broadest range of degradation machineries including, but  not limited to, the ubiquitin-proteasome system

3:30 pm Systematic Targeted Protein Degradation using Functional Proteomics

Synopsis

  • In order to break out of current chemical space limitations, a new method working on the same level as small molecules is required
  • PhoreMost has developed a phenotypic functional proteomics platform to screen millions of peptide “shapes” in live cell assays for protein degradation
  • Using this functional screening approach, we identified novel E3 ligands and peptide-based PROTACs

4:00 pm Afternoon Refreshments & Poster Session

Exploring Autophagy & Antibody Fragment Approaches to Induce Selective Degradation

4:30 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

5:00 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

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