CBP and EP300 Degraders: A Tale of Two Selectivities

Targeted protein degradation as a therapeutic modality has experienced an explosion in research the past several years resulting in advancements of numerous degraders to the clinic addressing a wide variety of disease indications. The strengths of this induced proximity modality include their catalytic mechanism, the ability to drug non-enzymatic targets which serve as scaffolds or protein interaction mediators, and introducing selectivity amongst highly similar family members.

In this talk, Danette highlights their work developing highly selective and potent degraders to CREB binding protein (CBP) and E1A binding protein (EP300), two paralog histone acetyl transferases that regulate a myriad of cellular processes implicated in numerous oncology diseases. Several classes of inhibitors have been developed to CBP/EP300, yet they have dual activity and exhibit tolerability challenges. Here we will investigate the mechanisms which lead to selectivity by biochemical and structural characterization of ternary complexes and cellular ubiquitination studies. With our selective CBP and EP300 degraders, we then demonstrate strong anti-proliferative and in vivo tumor growth inhibition across numerous oncology indications dependent on either CBP or EP300, each showing an improved therapeutic window as compared to dual inhibition.

00:00 Welcome and Introduction
11:37 DH Features
14:10 Presentation
52:25 Q&A

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Recorded on May 8th, 2025, as a Drug Hunter Flash Talk.

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