| Autor: |
Cheng-Sánchez, Iván, Gosselé, Katherine, Palaferri, Leonardo, Laul, Eleen, Riccabella, Gionata, Bedi, Rajiv K., Li, Yaozong, Müller, Anna, Corbeski, Ivan, Caflisch, Amedeo, Nevado, Cristina |
| Zdroj: |
JACS Au; September 2024, Vol. 4 Issue: 9 p3466-3474, 9p |
| Abstrakt: |
We present the development of dCE-2, 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 dCE-2was 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, dCE-2’s remarkable protein degradation activity stems from its good cooperativity, which we demonstrate by the characterization of its ternary complex formation both in vitroand in cellulo. 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. |
| Databáze: |
Supplemental Index |
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