Abstract 3841: Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation

Abstract CREB-binding protein (CBP, CREBBP, KAT3A) and E1A-binding protein (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators and transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain that catalyzes the histone H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such as enhancers and promoters. Transcription factors associate with stretches of H3K27ac marks (known as ‘super-enhancer’ elements) and result in gene transcription that ultimately establishes cell identity and fate. They are implicated in cancer pathology, and small molecule inhibition of the bromodomain (BRD) or HAT domain of CBP/p300 are considered promising therapeutic strategies for a number of cancer types. CBP and p300 are highly homologous but have distinct roles that have to date been hard to delineate, since small molecule inhibitors developed to date are unable to selectively target each protein independently. Additionally, small molecule inhibitors that target individual domains are unable to entirely abrogate the full functionality of CBP/p300. A bromodomain-recruiting dual CBP/p300 PROTAC Degrader ‘dCBP1’ was therefore recently developed to provide a chemical tool to explore the phenotypic consequences of CBP/p300 chemical knockdown. A further study demonstrated that it is possible to degrade p300 with some selectivity by converting a CBP/p300 dual HAT-domain inhibitor into a PROTAC, called ‘JQAD1’. We have used a different HAT-domain recruiting ligand to develop novel PROTACs that elicit proteasome-mediated degradation of p300 with significantly enhanced selectivity over CBP, compared with JQAD1. We additionally demonstrate a faster onset of degradation for lead PROTAC molecules and present data exploring the consequences of selective p300 degradation in CIC-DIX4 sarcoma. Citation Format: Graham P. Marsh, Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple. Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3841.