Abstract A060: Discovery of potent and selective EP300 degraders with anti-cancer activity

Abstract

Abstract E1A binding protein (EP300) and CREB binding protein (CBP) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcriptional co-activators. Dysregulation of one or both proteins has been implicated in various cancers, and functional genomic screens have demonstrated a bidirectional synthetic lethal relationship between the two genes in tumor cells. Due to the high homology between EP300 and CBP, identifying chemical matter that selectively targets EP300 or CBP has proven challenging. Here, we describe a potent, highly selective heterobifunctional degrader of EP300 with biological activity in CBP-deficient and EP300-dependent tumor cells. This compound achieves robust degradation of EP300 in vivo at doses that sustain EP300 degradation with minimal effects on CBP protein level. Targeted degradation of EP300 protein resulted in a stronger suppression of cell growth and survival than targeting the bromodomain or HAT activity of EP300/CBP with small molecule inhibitors. Strong anti-proliferative effects have been demonstrated in multiple cancer types, including lymphomas and prostate tumors, highlighting the essential role of EP300 in the malignant phenotype of these tumors. Citation Format: Mark Zimmerman, Darshan Sappal, Ammar Adam, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie DiBernardo, Thomas Dixon, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Laura LaBonte, Danette Daniels. Discovery of potent and selective EP300 degraders with anti-cancer activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A060.