Abstract 6287: Selective CBP degradation shows superior potency and differentiated biological activity compared to small molecule inhibitors

Abstract

Abstract CREB binding protein (CBP) and E1A binding protein (p300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in a variety of cancers, and functional genomic screens have exhibited a bidirectional synthetic lethal relationship between the two genes in many cancer indications. Due to the high homology between CBP and p300, identification of selective chemical matter that specifically and directly targets CBP has proven challenging. Small molecule inhibitors (SMIs) targeting the HAT or bromodomain of CBP/p300 have been developed, however these agents are not selective for either paralog and inhibit both proteins equally, potentially limiting their clinical application. Herein, we describe the biological activity of selective, potent CBP degraders and show differentiation from SMIs. Citation Format: Laura La Bonte, Darshan Sappal. Selective CBP degradation shows superior potency and differentiated biological activity compared to small molecule inhibitors [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 6287.