TPD Assay Development & Screening Focus Day
Monday, October 28 2024
8:00 am Check-in & Morning Coffee
8:45 am Chair’s Opening Remarks
Novel Assay Design & High Throughput Screening Approaches to Accelerate Degrader Discovery
9:00 am Discovering & Characterizing Latent E3 Ligase Protein-Protein Interactions Against 150 Therapeutic Targets
Synopsis
- Over 100 protein-protein interactions were identified between therapeutically relevant targets and a diverse set of ligases
- A subset of these interactions was further characterized using site-directed mutagenesis to define the interface and explore the ability to modulate the interaction
- These protein-protein interactions were used to prioritize small molecule discovery campaigns aimed at identifying molecular glues
9:30 am MicDrop – Phenotypic DEL Screen in Droplets for TPD
Synopsis
- Introduction to the concept of directed serendipity, a small-molecule equivalent of directed evolution enabled by DNA-encoded molecular glue library
- Overview of MicDrop, a phenotypic DEL platform enabled by droplet microfluidics and DNA-encoded one-bead one-compound library technology
- Walk-through of POI degradation screen data demonstrating the robustness of the platform with bead replicates and discovery of new glue degrader hits
10:00 am Predicting & Optimizing the Selectivity Profiles of Novel CELMoD Compounds
Synopsis
- Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing degradation of neosubstrate off-targets is complicated by the ternary nature of the complex formed between the POI, CRBN, and the CELMoD agent
- Herein we disclose an analysis of our glutarimide CELMoD library using a simple algorithm to identify the interpretable chemical features correlated with selectivity profiles and general cytotoxicity
- We also disclose simple multiparameter optimization (MPO) functions for each neosubstrate using two to three parameters to predict whether new molecules will likely have undesired off-target degradation activity
10:30 am Morning Break & Networking
11:30 am Deep Proteomics Screening Enables the Discovery of Novel Molecular Glue Targets
Synopsis
- High throughput proteomics screening of Cereblon-focused molecular glue library
- Identification of potent and selective molecular glue degrader for novel target
- Mechanistic profiling highlighting ubiquitinomics and mutational studies
12:00 pm Discovery of Novel E3 Ligase Binders via Rapid Screening of DNA-encoded libraries
Synopsis
- DNA-encoded library technology enabled the identification of novel binders for buckets of E3 ligases in a cost-efficient way
- Examples of potent binders for both ubiquitous E3 and tissue specific E3 Ligases directly from DEL
- Refined workflow towards ligase binder and PROTAc discovery at GSK
12:30 pm Networking Lunch Break
Unearthing New Opportunities in Indications & Modalities with Tailored Assay & Screening Design to Create New Avenues for Your Candidate
1:30 pm Optimising Proteolysis Targeting Chimeras (PROTACs) for Oral Drug Delivery
Synopsis
- Outlining our approach towards target selection.
- Defining the key principles that govern oral absorption for bRo5 compounds.
- Extrapolating trends and conclusions drawn from the data analysis of AZ compounds.
2:00 pm A Novel Protein Degradation Modality to Address Multiple Diseases
Synopsis
- Screening and discovery of new small molecules to promote protein degradation
- Unique protein degradation modulation that holds promise as a new therapeutic approach
- Proof-of-concept data in an animal disease model
2:30 pm Afternoon Break & Networking
Advancing New Ligase & New Ligand Understanding with Novel In Vitro & In Vivo Assay Design to Expand the Therapeutic Potential
3:00 pm Discovery of Novel E3 Ligands for Targeted Protein Degradation
Synopsis
- Uncovering the catalytic mechanism to achieve higher efficacy, the ability to target previously undruggable proteins and the potential to deliver drug activity to selective tissues in TPD
- Demonstrating how E3 ligands hold the key to realize the full potential of TPD but are currently limited
- Discussing our rationale and efforts in discovering novel E3 ligands for targeted protein degradation
3:30 pm Robust Cullin-RING Ligases Employ Geometrically Optimized Catalytic Partners for Substrate Targeting
Synopsis
- Cullin-RING ligases collaborate with multiple distinct E2s and the ARIH1 ubiquitin ligase to efficiently target thousands of protein substrate for ubiquitylation
- What in vitro assays demonstrate high predictive value towards degrader drug efficacy? How can this be optimized?
- Does in vitro ubiquitin ligase efficiency correlate with cellular neo-substrate degradation?
4:00 pm Discovery & Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease
Synopsis
- A phenotypic screen identified inducers of fetal hemoglobin to treat SCD
- Subsequent target elucidation identified CRBN dependent degradation of the transcription factor WIZ as driver of HbF induction
- Med chem optimization resulted in molecules with improved WIZ degradation selectivity and in vivo PK/PD and efficacy and candidates for development