Explore the Agenda
8:00 am Morning Coffee & Check-In
8:50 am Chair’s Opening Remarks
Improving Covalent Hit ID by Prioritizing Translation Ready Starting Points & Optimizing Screening Toolkits
9:00 am Actionable Decisions & Strategic Risk in Covalent Drug Discovery
- Interrogating covalent and reversible-covalent hits in the absence of a clear hypothesis to identify the truly functional system and define allosteric modulation strategies
- Uncovering mechanism beyond inhibition by revealing PPI disruption as the primary driver of efficacy through target engagement and mass spec validation
- Applying context dependent reversibility and chemical risk assessments to make decisive go/no go calls, advancing one program through preclinical safety while strategically discontinuing another
9:30 am Proteome-Wide Live-Cell Covalent Screening Reveals Physicochemical Drivers of Promiscuous Labeling & Design Principles for Selective Covalent Libraries
- Introducing the IMTAC TM proteome-wide cell-based screening platform
- Interrogating proteome-wide screening data to characterize compound reactivity and uncover patterns that contribute to selectivity or promiscuity of covalent compounds
- Refining covalent library design strategies to minimize promiscuity and eliminate nonproductive compounds, enabling more efficient, higher-quality hit identification
10:00 am Strategic Deployment of Kinetic Assay Technologies to Accelerate Covalent Drug Discovery
- Balancing throughput, cost, and data quality when selecting kinetic potency assay for early-stage covalent discovery
- Designing kinetic and dose-response assays to support efficient lead generation across diverse activity profiles
- Adapting assay platforms throughout lead optimization to accurately evaluate increasingly potent covalent compounds
10:30 am Morning Break & Networking
11:00 am Mass Spectrometry-Based Kinetic & Site-Specific Profiling of Covalent Inhibitors Targeting VRK1
- VRK1 is a synthetic lethality defined target in VRK2-low cancers
- Presenting our strategy for inhibitor discovery that utilized a focused covalent library, intact protein MS, and cellular cysteine mapping
- Demonstrating that mass spectrometry–based profiling can effectively identify covalent, isoform-selective inhibitors of VRK1
11:30 am The Evolution of the Novartis Covalent Library & Its Application
- Critical understanding of the chemical content of a library dictates success and strategies
- The path to augment the compound collections will be discussed along with recent highlighted successes following screening campaigns of this content
- Focus areas will be highlighted and innovation mechanisms discussed
Applying Computational & AI Enabled Approaches to Optimize Covalent Design Decisions Across Reactivity, Selectivity & Translation
12:00 pm Accelerating Covalent Drug Design by Improving Prediction of Binding Reactivity & Reducing Experimental Iteration Through Physics-Based & Data-Driven Models
- Assessing strengths and limitations of QM informed, physics based and ML driven approaches for modelling covalent systems
- Comparing predictive performance for reaction feasibility, binding geometry and adduct stability
- Integrating computational predictions with experimental validation to reduce synthesis burden and cycle time
12:30 pm Chemistry on the Right Target: The Expedition Medicines ML-forward Platform to Drug the Undruggable
- A reaction 1st paradigm for hit generation built on industry leading chemo-proteomics capabilities, novel library design, and machine learning on the highest quality data
- First-principles (physics) drug discovery accelerated by AI based on the three pillars (data engine, accurate physics at scale, ground truth data at scale)
- Reviewing progress against selected pipeline projects against highest value targets
1:00 pm Lunch Break & Networking
Designing PK/PD & DMPK Strategies that Reflect Irreversible Target Engagement & Inform Translational Planning
2:00 pm DMPK Strategy for Irreversible Covalent Inhibitor to Guide the Translation From Preclinical to Human
- DCN1, a novel target for fetal hemoglobin induction for Sickle cell disease, was discovered by the innovative transcriptomic platform at Cellarity
- Covalent inhibition of DCN1 was designed to achieve the desired pharmacology
- Developing IVIVE strategy to predict human clearance of covalent inhibitors and applying target turnover informed PK/PD model for predicting human efficacious dose
- Integrating PK/PD modeling with target occupancy data to guide the translation from preclinical models to human
2:30 pm Translating Covalent Drug Candidates from Concept to Clinic: DMPK & Clinical Pharmacology Strategies for Patient Benefit
- Defining the critical DMPK and clinical pharmacology considerations needed to successfully translate covalent drug candidates from discovery into clinical development – spanning dose selection, regimen design, clearance prediction, and the exposure-response relationships unique to irreversible mechanisms
- Leveraging cross-industry insights from a multi-company consortium to identify common challenges and best practices in progressing covalent therapies, with a focus on overcoming bottlenecks in dose finding, safety assessment, warhead reactivity characterization, and clinical study design
- Establishing practical guidance for bridging preclinical and clinical decision-making – including the implications of endogenous protein binding, which studies are essential vs. avoidable, and how to optimize development strategy to maximize the likelihood of regulatory success and patient impact