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Summer 2024 challenge: phase 1 contestant

Development of Molecular Glue Protein Degraders for Neurodegenerative Diseases

Fereshteh Azimian, University of south carolina, Columbia, United States

Targeted protein degradation (TPD) is an emerging therapeutic approach that aims to eliminate disease-causing proteins by recruiting them for rapid destruction via the ubiquitin-proteasome system (UPS) pathway. The aggregation of misfolded proteins plays a crucial role in the development of the neurodegenerative diseases. To combat protein aggregation, strategies that enhance autophagy are being explored. TPD leverages “molecular glue” protein degraders, which facilitate the connection between an E3 ligase enzyme and disease-causing proteins, leading to enhanced ubiquitination and subsequent degradation. Here, we focus on developing molecular glues to facilitate connect between the aggregated proteins in neurodegenerative disease such as amyloid beta (Aβ) and phosphorylated tau with the E3 ligase. This led to degradation of disease-causing proteins by bringing the proteasome into proximity with them. Molecular glues offer new therapeutic avenues for addressing unmet medical needs.
Fereshteh intends to achieve the following milestones:
  1. Virtual screening to find molecular glues to facilitate connect between the neurodegenerative disease-causing and E3 ligase proteins
  2. Biological evaluation of identified Hits for interaction with E3 ligase
  3. Lead optimization of identified Hit molecular glues