Molecular glue discovery has historically been challenging because biological activity depends on forming a productive ternary complex between the target protein, small molecule, and recruited effector. However, a recent study represents an important shift from serendipity-driven discovery toward systematic molecular glue engineering.
Researchers developed a target-first, high-throughput strategy by modifying ENL and BRD4 ligands with 3,163 diverse chemical building blocks, converting conventional ligands into degraders through remodeling of a single solvent-exposed surface. These subtle chemical changes enabled the creation of new proteinโprotein interfaces, altered cooperativity, and promoted selective degradation.
The approach identified two new degraders: dHTC1, an ENL degrader that recruits CRL4^CRBN through a cooperative proteinโprotein interface, and dHTC3, a BRD4 molecular glue that recruits the previously unexplored E3 ligase SCF^FBXO3.
This work demonstrates that molecular glue discovery can move beyond chance discoveries toward a scalable, target-driven platform. By expanding the chemical space available for proximity-based therapeutics, this strategy offers new opportunities to address previously challenging or โundruggableโ proteins while revealing new biological mechanisms through unbiased screening.
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