Conference Day Two
8:30 am Light Breakfast & Check-In
8:55 am Chair’s Opening Remarks
Advancing a Chemoproteomic Toolkit for Enhance the Discovery of “Ligandable” Residues for Targeting by Small Molecule Drugs
9:00 am Expanding the Scope of Photo-Releasable Modalities to Enable Drug Target Identification & Ligandable Residue Mapping
Synopsis
- Development of oxadiazolines as photo-reactive modalities for small molecule functionalization in complex chemical reactions, allowing the exploration of a larger chemical space
- Pressure testing oxadiazolines for robust target engagement with known inhibitors via chemoproteomics and applications for FBDD screens
- Expanding the chemical toolkit with novel chemistries that provide spatial and temporal controlled modification of tryptophan
- Charactering novel chemistries to profile reactive residues across the proteome
9:30 am Identifying Fragments for Covalent Drug Discovery by Combining Intact Ms Analysis on Recombinant Proteins with Cellular Chemoproteomics Approaches
Synopsis
- Discussing the approach of using both intact MS analysis for the high throughput screening of covalent fragments against recombinant proteins, with lower throughput chemoproteomics approaches – in cell competition between compound and desthiobiotin iodoacetamide (DBIA) – to determine target engagement and selectivity against native proteins
- Evaluating in-cell DBIA results to identify protein degraders and stabilizers
- Understanding the “ligandibility” of Cysteine residues to identify optimal cysteine residues that can be leveraged for drug development
10:00 am Developing a Proteomics Toolkit for the Discovery, Translation & Characterization of Small Molecule Degraders
Synopsis
- Characterizing degradation profiles and selectivity across various models to understand off-target activity and safety
- Integrating targeted proteomics for higher throughput assessment of degradation kinetics and benchmarking
- Utilizing proteomics to characterize the turn-over of protein of interest in models to inform the design degraders
10:30 am Morning Break & Networking
Enhancing Proteomics Workflows: Merging Discovery & Structural Insights to Enhance Drug Discovery & Development
11:30 am Panel Discussion: Integrating Discovery with Emerging Advances in Proteomics to Create Seamless Workflows that Yield Actionable Insights
Synopsis
- How can we complements discovery proteomics with structural data to unravel the “pocketability” of amino acid residues?
- What are the challenges and innovations in techniques to map protein networks within tissues and how can they complement discovery proteomics?
- What assays can we use to complement mass spectrometry and obtain comprehensive data on protein-protein interactions
12:15 pm Lunch Break & Networking
Innovative Approaches to Target Engagement: From CNS-Penetrant Degraders to High- Throughput Proteomic Readouts
1:15 pm Pre-clinical Characterization of Orally Bioavailable CNS-Penetrant Degraders for the Treatment of Multiple Sclerosis
Synopsis
- Selectivity Profiling: Assessing the specificity of the degrader candidate across a range of targets
- Target Engagement Assays: Measuring the binding and interaction of the degrader candidate with its intended target
1:45 pm Accelerating the Throughput of Cellular Thermal Shift Assays for Mass Spectrometry-Based Proteomic Readout & Creating “Drug Fingerprints”
Synopsis
- Automating CETSA workflows to enhance reproducibility and throughput and facilitate target-engagement studies
- Assessing TMT and label free methods in the context of small molecule-induced changes to protein stability
- Applying these improvements to the drug discovery pipeline and developing a protein stability-based “Drug Atlas”
2:15 pm Afternoon Break & Networking
Unravel Binding Profiles Through Hydrogen/Deuterium Exchange & Ubiquitin-Specific Proximity Labeling Approaches for Advancing Drug Discovery & Development
3:15 pm Hydrogen/Deuterium Exchange and Protein Oxidative Footprinting with Mass Spectrometry Collectively Discriminate the Binding of Small Molecule Therapeutics to Bcl-2
Synopsis
- OX-MS analysis clearly distinguishes the binding profiles of two drugs to BCL-2 demonstrating its ability to complement HDX-MS in screening candidate compounds during drug discovery and development
- OX-MS provides nuanced insight into the nature of small molecule complexes with proteins through sensitivity to structural changes resulting from both direct binding and allostery
- The precision and ease of implementation of Fenton chemistry mediated OX-MS has the potential to enhance pharmaceutical research and therapeutic development pipelines
3:45 pm Neo-substrate Discovery by Ubiquitin-Specific Proximity Labeling
Synopsis
- Introducing an unbiased method to identify E3 ubiquitin ligase substrates with high specificity
- Revealing novel insights about molecular glue degraders and PROTACs by studying substrate ubiquitylation
- Leveraging information on protein ubiquitylation for informing discovery of degraders and other E3 ligase modulators