Leveraging High-Throughput Proteomics and AI-Based Protein Folding to Accelerate VAV1 Molecular Glue Discovery

Novel CRBN molecular glues induce selective VAV1 degradation via a unique non-canonical RT-loop degron, with potency enhanced by conformational restriction strategies.

• Why it matters: Targeting VAV1 is crucial for treating hematological malignancies and autoimmune diseases, but understanding and optimizing molecular glues for diverse degrons remains a challenge, limiting therapeutic development.
• What they did: The study employed unbiased proteomics, AI-driven structural modeling, and FEP+ calculations to identify and optimize phenyl-glutarimide derivatives, revealing a new VAV1 degron and guiding rational design.
• The result: This integrated approach enabled the discovery of potent degraders, clarified recognition of diverse degron motifs, and established a workflow for prospectively ranking and improving molecular glue efficacy, broadening therapeutic possibilities.