Development of p300-Targeting PROTAC® Degraders with Enhanced Selectivity and Onset of Degradation

Targeted protein degradation using heterobifunctional molecules has led to significant advancements in cancer therapy development. CREB-binding protein (CBP) and E1a-binding protein (p300) hold great promise as therapeutic targets for multiple cancers. However, current small molecule p300/CBP inhibitors are hindered by on-target toxicity, acquired resistance, and a lack of selectivity needed to distinguish between closely related proteins. 

In this study, we developed p300-targeting degraders with improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader, JQAD1. These degraders serve as valuable tools for further exploration of p300 degradation as a therapeutic strategy. 

Download this PROTAC degrader development poster to explore:

• Utilization of commercially available degrader building blocks to synthesise novel p300-targeting PROTAC degraders 

• Methods for monitoring degradation, including automated capillary electrophoresis using Simple Western™ assays 

• Assessment of on-target toxicity using ATP viability assays