Conference Day 2
All times in EDT
8:30 am Morning Coffee & Chair’s Opening Remarks
Optimizing High-Throughput, Systematic Screening & Identification of Ligase Ligands
9:00 am Discovery of Novel E3 Ligands for Targeted Protein Degradation
Synopsis
- Discovery of new E3 ligands represents a significant opportunity and major challenge for targeted protein degradation
- Cullin-RING family E3 ligases are particularly suitable for TPD
- Discovery of novel E3 ligands for TPD at Cullgen
9:30 am Chemical Targeting of WDR Domain Containing E3 Ligases
Synopsis
- WDR domain is a common substrate-binding domain in E3 ligases
- Using AI for WDR hit discovery
- Discovery of DCAF1 ligands
10:00 am Application of DNA-Encoded Libraries to Discover Small Molecules for E3 Ligase Modulation
Synopsis
- Outlining the use of Nurix’s DELigase platform to discover binders to E3 ligases
- Identification and optimization of ligands with unique mechanism of action
- Prospects for use of E3 ligase binders for TPD/therapeutic application
10:30 am Identification of Ligands for E3 Ligases
Synopsis
11:30 am Morning Break & Poster Session
Synopsis
As the landscape of innovative discovery and development efforts to target ubiquitin ligases for therapeutic application expands, it is more important than ever to collaborate and learn with your peers as we continue to advance ligase targeted therapies through discovery. Join our dedicated session to share your latest data and have a first look about what your peers are working on!
The Landscape of E3 Ligases Targeting for Successful Degradation Applications
12:00 pm Panel Discussion: Translational Role of E3 Ligases in Therapeutics for Disease
Synopsis
As covalent targets successfully progress through clinical phases, and molecular glues propose it is critical that we consider the optimum safety, translation, and development of effective therapeutics. From tissue and cell specificity, preclinical translation and toxicity effects, discussion about the all-important translation of this promising therapeutic begins here.
- What are the likely viable therapeutic applications of E3’s, from PROTACs and beyond?
- What are the important safety considerations, and PK/PD that must be touched?
- Translation into clinic poses inherent challenges – what will be the bottleneck for progression?
12:30 pm Development of Chemical Probes & E3 Ligase Recruiting PROTAC Handles Targeting SOCS2
Synopsis
- The structure of guided design and development of potent covalent and non-covalent binders targeting SH2 domain of SOCS2
- The evaluation of several phosphate masking prodrugs to demonstrate cellular SOCS2 engagement by the binders
- Differential cellular expression profiles of SOCS proteins provide an opportunity to utilize SOCS recruiting PROTACs to tune tissue/disease specific degradation of target proteins
1:00 pm Lunch & Networking Break
Benchmarking Approaches for Optimal Ternary Complex Modelling
2:00 pm In-depth Topological Characterization of a PROTAC Ternary Complex by Mass Spec-based Strategies
Synopsis
- Applications of MS in biophysical characterizations of noncovalent protein complexes
- MS-based strategies for higher order structure characterization of PROTAC ternary complex
- Future perspectives
2:30 pm Ternary Complex Structure Prediction by Combining Molecular Simulations with Hydrogen Deuterium Exchange
Synopsis
- Reviewing how the formation of the POI-degrader-E3 ternary complex is central to the targeted protein degradation process.
- Using a single conformation (e.g., x-ray crystal) neglects the complex dynamic nature of the non-native induced proximity complex
- Combining experimental biophysical data (HDX-MS) with molecular dynamics (MD) simulations can significantly improve ternary complex structure prediction, reaching atomic resolution
- Outlining how this approach can be used to identify additional low-energy conformations of the ternary complex that are not the revealed by static structures like those obtained from x-ray crystallography
3:00 pm Driving Drug Discovery by Accelerated Target Degradation
Synopsis
- The Imids serve as a molecular glue that subverts the functional E3 ubiquitin ligase complex allowing it to bind neosubstrates and subject them to ubiquitination and subsequent degradation: to exploit this mechanism an expansive library of Imids and related CRBN binders was created
- This chemical atlas has been screened using a mammalian two hybrid system developed at Orionis Biosciences which identifies novel neosubstrates that are “glued” and recruited to the small molecule-CRBN binary complex
- Thus far, in excess of 100 proteins have been screened in this system, leading to the identification of novel molecular glues that degrade proteins previously considered and described as undruggable