Day Two

Thursday, December 14, 2023

8:45 am Morning Coffee

9:20 am Chair’s Opening Remarks

Inventing Novel Chemistry: Devising New Warheads to Access Targets Beyond Cysteine & Peptides

9:30 am Targeting Arginine & Serine Residues Through Covalency to Expand the Scope of Covalent Drugs

  • Ziyang Zhang Professor of Chemistry & Chemical Biology, University of California Berkeley

Synopsis

  • Modifying screening platforms to discover covalent binders for non-cysteine residues such as arginine and serine
  • Exploiting chemical reactivity to create compatible warheads for non-cysteine residues
  • Identifying, characterizing and leveraging the right micro-environment to promote covalent modification of serine and arginine

10:00 am Kinetic Activity Assays Enable Data-Rich Decisions for Improved Covalent Drug Discovery

Synopsis

  • Fluorogenic sensor peptides provide direct, continuous and quantitative monitoring of kinase & phosphatase enzyme kinetics—a progress curve in every well
  • Deep kinetic characterization provides fit-for-purpose assessments for irreversible [kinact, KI, kinact/KI)] or reversible [residence time (τ), IC50 or Ki] inhibitors
  • Kinetic profiling with >400 wild-type kinases at low or high ATP provides superior selectivity assessments with insight into compound-dependent kinetics & MOA 

10:15 am Designing Reversible Covalent Boron Warheads to Target Multiple Amino Acid Residues

Synopsis

  • Understanding the pros and cons of reversible covalent boron warheads to effectively utilize them against protein targets
  • Balancing the reversible affinity binding and warhead reactivity to drive effective covalent interactions
  • How to leverage reversibility to minimize off-target toxicity while building in high target specificity

10:45 am Morning Break & Networking

11:15 am Panel Discussion: How Can We Build Covalent Chemistries that Drive Selectivity & Open New Unvalidated Target Spaces such as Non-Cysteine Residues

  • Ziyang Zhang Professor of Chemistry & Chemical Biology, University of California Berkeley
  • Jeff McKenna Director, Novartis AG
  • Lei Wang Professor, University of Califorina, San Francisco
  • Ivan Cornella Chief Scientific Officer, Covant Therapeutics

Synopsis

  • What are some example novel warheads that are being explored to advance covalent modification to new acid residues?
  • How can we effectively target “soft” nucleophiles that are not as reactive as cysteine?
  • Are there unvalidated target spaces that have not yet been drugged which covalency can open up? Such as through nonsmall molecule drugs or by going after non-peptide targets?

12:00 pm Lunch Break & Networking

Leveraging Existing Covalent Platforms & Drugs as Case Studies to Inform Novel Drug Development

1:00 pm Comprehensive Solutions to Covalent Drug Discovery at WuXi AppTec

  • Jason Deng Senior Director and Boston Site Head, Discovery Biology, WuXi AppTec

Synopsis

  • An overview of current capabilities in covalent drug discovery at WuXi AppTec, including library collections, screening methods and follow-up services
  • Detailed introduction of covalent DEL, FBDD and HTS platforms
  • Discussion of recent case studies

1:15 pm Advancing Covalent Hit-Finding: Lessons from Diverse Covalent Screening Campaigns

Synopsis

  • Which screening strategies have proven effective in the identification of novel covalent inhibitors
  • Factors to consider in the design of covalent screening libraries
  • Hit triage and the role of structural biology in accelerating hit-to-lead efforts

1:45 pm Unlocking New Frontiers in Undruggable Disease Targets

Synopsis

  • Creating a purpose-built platform to enable covalent drug discovery
  • Accelerating hit-to-lead optimization through AI and data 
  • Building best-in-class covalent medicines 

2:15 pm Accelerating Drug Discovery of Covalent Inhibitors with Improved Triaging & Optimization of Compounds

Synopsis

  • Elucidating methodology to better triage drug discovery program starting points
  • Optimization of covalent inhibitor lead structures to accelerate lead to drug-like compound pipeline
  • Discussing tools to predict the extended PD effect of your covalent compounds

2:45 pm Afternoon Break & Networking

3:15 pm Chemical Biology Enabled Covalent Drug Discovery from Hit to Clinic

  • Brent Martin Vice President - Chemical Biology, Scorpion Therapeutics

Synopsis

  • Employing automated sample preparation for in-cell cysteine covalent ligand profiling by deep proteomics
  • Conducting occupancy modeling and Kinact/Ki to drive hit finding and structure-activity relationship (SAR)
  • Designing chemical probes for target occupancy profiling throughout preclinical development

3:45 pm Discussing Drug Discovery Applications of Covalent Fragments in Neuroscience

Synopsis

  • An overview of reactive cysteines in neuroscience focused research
  • Revealing approaches for covalent fragment screening and drug discovery applications for neuroscience
  • Conducting chemoproteomic profiling of covalent XPO1 inhibitors to assess target engagement and selectivity

4:15 pm Discovering JDQ443: Using an Inhibitor of KRAS G12C as Case Study for Covalent Drug Development

Synopsis

  • Identification of a novel series of KRAS G12C inhibitors by structure based design
  • Designing a covalent warhead and scaffold for KRAS G12C through modern medicinal chemistry
  • Discussing the discovery of JDQ443 as a case study for covalent drug discovery

4:45 pm Chair’s Closing Remarks

5:00 pm Close of Covalent Drug Discovery Summit

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