High-throughput ligand diversification to discover chemical inducers of proximity.

High-throughput chemical modification of ligands yields 3,163 compounds, leading to the discovery of novel chemical inducers of proximity with therapeutic potential.

• Why it matters: Understanding and controlling biomolecular interactions is crucial for cellular regulation and drug development, yet current methods rely heavily on chance or rational design, limiting discovery of effective chemical inducers.
• What they did: Using sulfur(VI) fluoride exchange-based high-throughput chemistry, researchers decorated ligands for ENL and BRD4 with diverse building blocks, screening for degrader activity and identifying new effectors.
• The result: The approach led to the identification of dHTC1, a selective ENL degrader engaging CRBN only after complex formation, and dHTC3, a molecular glue that dimerizes BRD4 to a novel E3 ligase, expanding proximity pharmacology tools.