8:30 am Morning Coffee & Networking

8:55 am Chair’s Opening Remarks

Assessing Assay Strategies to Expand Beyond VHL & Cereblon & Find New E3 Ligases

9:00 am The Plexium Platform Expands the Repertory of E3 Ligases in TPD Drug Discovery

Synopsis

• Overview of the Plexium screening platform: Multiple detection readouts to identify monovalent degrader or molecular glue effects in cells
• Case study of new E3 ligase discovery using monovalent degrader identified in protein degradation screening
• E3 ligase redirection using RNAseq screening

9:30 am Discovery of New E3 Ligase Ligands Through Proximity Labelling- Based Proteomics

  • Dongwen Lyu (Lv) Assistant Professor/ Research, Department of Biochemistry & Structural Biology at UT Health San Antonio

Synopsis

• Natural products are a great source for the discovery of new E3 ligase ligands
• Proximity biotinylation combined with mass spectrometry is a powerful method to identify E3 ligases recruited by novel E3 ligase ligands
• Assays can be used to verify the formation of binary and ternary complexes

10:00 am Using PROTEINi® to Develop Novel Degraders: Assays & Principles

Synopsis

• Phenotypic screening for protein degraders using PhoreMost’s PROTEINi technology has identified several novel bio-active degron peptides and their corresponding E3 ligases
• Target-specific screening allows the development of biological bifunctional protein degrader molecules
• We’ll show how the PROTEINi-E3 ligase interaction is used to inform and accelerate the development of small molecules that interact with E3 ligases to build novel heterobifunctional degrader molecules and discuss the critical assays and data required to develop them

10:30 am Scientific Poster Session

Evaluating Target Engagement Assays to Optimize Degrader Design

11:30 am CoraFluor Enabled TR-FRET Assay Strategies for Facile PROTAC Profiling

  • Ralph Mazitschek Assistant Professor, Massachusetts General Hospital/ Harvard Medical School

Synopsis

• Novel TR-FRET based strategies utilizing CoraFluors for the quantitative characterization of:
• Target engagement
• Target abundance in whole cell lysates
• Ternary complex formation

12:00 pm Round Table: Comparing the Protocol Across Degrader Approaches
Moderated By:

Synopsis

• What are the key differences in target engagement from traditional PROTACs to emerging approaches?
• How can the scope be widened?
• Looking at mass spec tools to support engagement assessment

 

12:30 pm Networking Lunch

Comparing Strategies to Assess Ternary Complex Formation

1:45 pm Integrating Multiple Assays to Enhance the Connectivity Between Ternary Complex Detection & Protein Degradation In Cells

  • Taosheng Chen Full Member (Professor) Director of High Throughput Bioscience Center, St. Jude Children’s Research Hospital

Synopsis

• Ternary complex formation is critical for target degradation
• Whether formation of a ternary complex results in target degradation is affected by multiple factors
• Coordinated use of biochemical, biophysical, and cell-based ternary complex formation assays will improve the predicting power of the assays

2:15 pm Characterization of the Recruitment of Proteins to Ligases By Molecular Glues

  • Charles Wartchow Associated Director, Global Discovery Chemistry, Novartis Institutes for Biomedical Research

Synopsis

  • The structural and biophysical characterization of the interaction of zinc finger proteins with Cereblon in the presence of molecular glues provides unique molecular insights
  • We developed robust SPR assays for characterizing the binding of small molecule glues and zinc-finger domains to Cereblon
  • For some zinc finger proteins, multiple zinc fingers are implicated in the interaction with Cereblon

2:45 pm Mastermind: Showcasing Emerging Technologies to Advance Degrader Discovery & Development & Get Next Generation Degraders to Patients Faster

  • Oscar Huang Principal Scientist, Biochemistry & Biophysics, Bristol Myers Squibb

Synopsis

• This mastermind is a great opportunity for the delegate audience and speakers to have an open, frank conversation about exciting new technologies such as AI, cryoEM, “function-first” strategies and how to address emerging challenges

15:15 pm Afternoon Break

Utilizing Computational Modelling as a Key Tool for Design & Optimization of Degraders

3:45 pm Rhapsody™, Monte Rosa’s in- silico Engine for Rational Design of Selective Molecular Glue Degraders

Synopsis

• Ternary complex models
• In- silico structure-based screening
• Generative glue designs

4:15 pm Molecular Property Prediction Using Machine Learning

  • Mridula Bontha Senior Research Associate, Machine Learning, Nurix Therapeutics

Synopsis

  • Optimization of targeted protein degrader molecules can be frustrated by an inability to predict ADMET properties for compounds with such non-traditional property profiles. Our analysis demonstrates how computable descriptors and intuition commonly used to navigate ADMET properties for small molecules fail to demonstrate correlation with experimental data generated from degraders
  • We demonstrated that with machine learning capabilities, we can build a single global model for chemical property prediction of compounds belonging to diverse chemical space. Machine Learning models achieving high accuracy in the prediction of several ADME properties (such as solubility and permeability) have been developed and deployed to assist in optimization campaigns
  • By machine learning standards, the quantity of experimental ADME data available for targeted degrader molecules is small. Despite this limitation, we demonstrate the ability of modern machine learning frameworks to learn and predict the structure property relationships for these unique compounds

4:45 pm Chair’s Closing Remarks

5:00 pm End of Inaugural TPD Assay Development & Screening Summit