Post Conference Focus Day

Post-Conference Focus Day

08:30 am | Morning Networking

8:50 am Chair’s Opening Remarks

Enhancing Target Engagement for PROTACs & Molecular Glues

9:00 am Addressing Target Selectivity & Target Engagement for PROTACs & Molecular Glues

  • Bomie Han Research Advisor, Quantitative Biology, Eli Lilly

Synopsis

  • Whole cell proteomics to address mechanism of action for protein degraders against cancer targets
  • MS-based in vitro method to discover natural targets and off-targets for PROTAC and molecular glues
  • Methods to quantify target engagement for PROTACs and molecular glues

9:40 am Quantitative Mechanistic Modeling of Covalent PROTACs

Synopsis

  • Development of mathematical model that incorporates covalency into heterobifunctional degraders to either E3 or target warhead
  • Insights into advantages of covalent E3 PROTACs to engage and degrade target proteins, and increase catalytic efficiency in TPD
  • Covalent binding to target can also confer benefits to overcome weak binding
  • Interplay between kinetics of covalent bond formation and degradation

10:10 am Enhancing Intracellular Concentration & Target Engagement of PROTACs with Reversible Covalent Chemistry

  • Jin Wang Professor, Baylor College of Medicine

Synopsis

  • Development of mathematical model that incorporates covalency into heterobifunctional degraders to either E3 or target warhead
  • Insights into advantages of covalent E3 PROTACs to engage and degrade target proteins, and increase catalytic efficiency in TPD
  • Covalent binding to target can also confer benefits to overcome weak binding
  • Interplay between kinetics of covalent bond formation and degradation

10:40 am | Speed Networking

Revealing Robust Technologies to Analyze Efficacy & Efficiency of Degraders

11:30 am Designing Ternary Complex Formation Assays to Identify & Characterize Protein Degraders

  • Taosheng Chen Director of High Throughput Bioscience Center, St. Jude Children’s Research Hospital

Synopsis

  • Ternary complex formation is critical for effective target degradation
  • The ternary complex can be regulated by modulators of the target, thus providing a mechanism for fine-tuning the efficacy of degradation
  • The mode-of-action and efficacy of protein degraders can be revealed by coordinated use of biochemical, biophysical, and cell-based ternary complex formation assays

12:00 pm Taking Nature’s Lead to Harness the Cell’s Protein Degradation Machinery

  • Laura Itzhaki Professor of Structural , University of Cambridge

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 these interactions to harness proteostasis networks and thereby manipulate protein stability and disease outcome
  • Libraries of target-engagement modules and degradation-inducing modules are combined with a mix-and-match format to find the best combination for effective knockdown of the target
  • The platform has the potential to reach diverse targets and co-opt the broadest range of degradation machineries including, but not limited to, the ubiquitin-proteasome system

12:30 pm Round Table: Your Thoughts on Whether Co-Operativity is Needed

Synopsis

Co-operativity is a controversial topic with lots of differing opinions and extensive research has been carried out to assess if positive cooperativity is necessary for potent protein degradation. This is your opportunity to share your thoughts on this topic. Do you think it’s necessary? Is it something you are looking at in your research? How might this affect the scope of PROTAC applications? How do you look at next generation design?

1:00 pm | Networking Lunch

Assessing Strategies of Expanding the E3 Toolbox to Optimize Therapeutic Benefit

2:00 pm Towards the Universal Druggability of E3 Ligases

  • John McGee Director & Scientific Founder, FogPharma

Synopsis

  • Helically constrained peptides are an emerging drug modality that allow the targeting of intracellular protein surfaces that are ordinarily inaccessible to small molecules or biologics
  • We have used our helix discovery platforms to discover and characterize binders for a diverse range of E3 ligases
  • High-resolution co-crystal structures of peptides bound to these E3 ligases reveal a variety of binding modes, and inhibition and activation mechanisms

2:30 pm PROTAC Development to Target an Endoplasmic Reticulum Membrane Protein

Synopsis

  • Discovery of a noval target class for PROTACs which is localized to the endoplasmic reticulum
  • Novel PROTAC target disclosure
  • PROTAC optimization, including structures

3:00 pm The Therapeutic Potential of CK1-Selective Degrader in Hematological Malignancies

Synopsis

  • How to find and optimize a molecular glue degrader and its therapeutic implication
  • Difficulties in lead optimization process of molecular glue degrader compared to PROTAC
  • CRBN vs novel E3 ligases as a molecular glue degrader platform

3:30 pm De Novo Identification of a Fully Synthetic FKBP12-FRB Molecular Glue

Synopsis

  • Assays for de novo identification of weak primary molecular glues
  • Identification of a fully synthetic small molecule molecular glue for mTOR
  • Optimization and biophysical characterization of molecular glues

4:00 pm Chair’s Closing Remarks & End of the Post-Conference Focus Day