Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.

Monovalent degraders can recruit two E3 ligases simultaneously to degrade SMARCA2/4, with tunable dependency on DCAF16 or FBXO22.

• Why it matters: Understanding how to control E3 ligase recruitment enhances the design of targeted degraders and addresses resistance mechanisms in protein degradation therapies.
• What they did: Using genetic screening, structural analysis, and mutational scanning, the study examined a monovalent MGD capable of engaging both CUL4 DCAF16 and CRL1 FBXO22, identifying key interaction sites and structural features.
• The result: The findings demonstrate that degrader E3 ligase dependency can be chemically and genetically tuned, enabling customizable degradation strategies and improved therapeutic potential.