p300/CBP Drug Discovery: Do Bifunctional Degraders Now Beat Classical Inhibitors?
- A perspective reviewing small-molecule inhibitors of the p300/CBP bromodomain and catalytic (HAT) domain, with emphasis on how the leading clinical compounds were optimized.
- It then follows the field's shift toward bifunctional proximity-inducing molecules, including PROTAC degraders.
- The article compares what each modality offers for these large, multidomain coactivators.
💡 Points
p300/CBP is a good test of when degradation earns its molecular weight: scaffolding functions that inhibitors leave intact are exactly what a degrader removes. The HAT-domain and bromodomain optimization stories are useful reading for anyone with a stubborn chromatin target. I'd read the degrader sections skeptically on paralog selectivity, since p300 and CBP are nearly identical.