DAY TWO

Thursday | February 20

8:00 am MORNING REFRESHMENTS

8:50 am Chair’s Opening Remarks

DESIGNING OPTIMIZED DEGRADER MOLECULES FOR MAXIMUM PENETRATION OF THE BBB & EFFICACY AT THEIR TARGET SITE WITHIN THE CNS

9:00 am Innovating the Design & Synthesis of Bifunctional & Molecular Glue Chemical Probes for Understanding CNS Therapeutic Concepts

Synopsis

  • Enabling rapid library synthesis and hit finding for bifunctional molecules to test CNS disease concepts
  • Developing new chemistries to aid the exploration of CNS-compliant chemical space for induced proximity modalities
  • Design and profiling of cellular chemical probes to identify actionable targets and effectors in the CNS

9:30 am Programmable Modulators of Undruggable Targets via Generative Language Models

  • Pranam Chatterjee Assistant Professor of Biomedical Engineering & Co-Founder (UbiquitX), Duke University

Synopsis

  • Generative language models can design selective peptide binders to any target, including those that are disordered and lack binding pockets
  • Peptide binders can be fused to E3 ubiquitin ligases or deubiquitinases, driving programmable target degradation of proteins such as GFAP and mHTT and stabilization of proteins, such as p53
  • These peptide-enzyme fusions can be readily encapsulated as mRNA in LNPs or encoded into AAVs for therapeutic delivery

10:00 am MORNING BREAK & NETWORKING

10:30 am Designing, Constructing & Screening Molecular Glue Libraries to Identify Potent & Selective Glues for Neurodegenerative Targets

  • Magnus Walter Senior Vice President Drug Discovery, Monte Rosa Therapeutics

Synopsis

  • A highly curated library of molecular glue degraders (MGDs) is a key component of QuEEN, our proprietary MGD discovery engine
  • Property-based design delivers MGDs with tuneable tissue-distribution profiles
  • Access to highly potent, selective and brain-penetrant MGDs

11:00 am Round Table Discussion: Breaking Barriers: Designing Optimized Degrader Molecules for CNS Targets

Synopsis

Selection of Target Proteins:

  • What criteria should be used to select target proteins for degradation in neurodegenerative diseases?
  • How do we prioritize targets based on disease relevance and druggability?

Design and Optimization of Degrader Molecules:

  • What are the key considerations in designing effective PROTACs (Proteolysis-Targeting Chimeras) and molecular glues?
  • How can we optimize the linker length, E3 ligase ligands, and target-binding moieties to enhance degrader efficacy and selectivity?

Mechanistic Insights and Structure-Activity Relationships (SAR):

  • How do the structural features of degraders influence their mechanism of action and degradation efficiency?
  • What are the latest advancements in understanding the SAR of protein degraders?

12:15 pm LUNCH

REVIEWING DEVELOPMENTS IN PRECISION TARGETING OF NEURODEGENERATIVE PATHWAYS FOR CNS DISEASES: TARGET SELECTION, PATHWAY ANALYSIS & ENGAGED MECHANISMS

1:15 pm Protein Folding Pathways Across Physiology & Therapy

  • Emiliano Biasini Co-Founder (Sibylla,) & Associate Professor, Centre for Integrative Biology (Cibio), University of Trento

Synopsis

  • Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), the approach could represent a new paradigm for drug discovery
  • Targeting Protein Folding Pathways: Our research highlights the therapeutic potentials of targeting protein folding pathways to treat neurodegenerative diseases
  • Mapping Cryptic Phosphosites in the Human Proteome: the discovery of cryptic phosphosites in proteins

1:45 pm Successful Use of Phenotypic Screening for Protein Degraders for Neurodegenerative Disease

  • Beth Hoffman Chief Executive Officer, Origami Therapeutics, Inc.

Synopsis

  • Keys for high-throughput screening
  • Expeditious characterization of hits using primary human cell models
  • Accelerating drug discovery using PK/PD models

2:15 pm AFTERNOON BREAK & NETWORKING

2:45 pm Successes and Challenges in Addressing Protein Degradation for Neurodegenerative Pathways

Synopsis

  • Updated information on targets in the pipeline
  • Landscape of current challenges
  • Outlook and opportunities for the future

3:15 pm Tau Degrader for Alzheimer’s & Primary Tauopathies: From Platform Development to Translation

  • Lili Zhang Senior Vice President & Head of Preclinical Development, Aprinoia Therapeutics Inc.

Synopsis

  • Overview of misfolded protein aggregates for targeted protein degradation
  • Review of technologies and pathways being pursued for tau degrader drug development
  • Future directions of translating tau degrader to drug in clinics

3:45 pm Chair’s Closing Remarks

3:50 pm END OF CONFERENCE

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