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

Monovalent degraders can recruit two E3 ligases, DCAF16 and FBXO22, to degrade SMARCA2/4, with ligase dependency being chemically and genetically tunable.

• Why it matters: Understanding how to control E3 ligase recruitment enhances the design of targeted degraders and may help mitigate resistance mechanisms in protein degradation therapies.
• What they did: Using orthogonal genetic screening, biophysical, and structural analyses, the study examined a monovalent MGD that recruits both ligases, identifying key residues and structural features influencing activity.
• The result: Single compound modifications can shift degrader preference between DCAF16 and FBXO22, and a single substitution can increase dependency on DCAF16, enabling customizable degradation strategies.