Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity.

We present the development of , a structurally novel PROTAC targeting the CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. The design of was based on the crystal structure of an in-house bromodomain (BRD) inhibitor featuring a 3-methyl-cinnoline acetyl-lysine mimic acetyl-lysine mimic discovered by high-throughput fragment docking. Our study shows that, despite its modest binding affinity to CBP/EP300-BRD, 's remarkable protein degradation activity stems from its good cooperativity, which we demonstrate by the characterization of its ternary complex formation both and . Molecular dynamics simulations indicate that in aqueous solvents, this active degrader populates both folded and extended conformations, which are likely to promote cell permeability and ternary complex formation, respectively.