Abstract 7186: Anti-cancer activity of potent and selective EP300 degradation in hematological malignancies

Abstract E1A binding protein (EP300) and CREB binding protein (CBP) are highly homologous acetyltransferase paralogs with demonstrated roles as transcriptional co-activators. Dual inhibition of EP300 and CBP has been reported to have anti-proliferative effects in several cancer types. However, it has also been reported to elicit thrombocytopenia, a toxic reduction in the number of platelets in the blood (Nicosia et al., 2023). Hematological malignancy lineages are particularly susceptible to EP300 loss (DepMap, Broad 2024), therefore, developing chemical matter that selectively targets EP300 has the potential to broaden the therapeutic window and improve tolerability. Historically, selectivity has been difficult to engineer due to the high sequence similarity between EP300 and CBP. Using the targeted degradation approach, we have developed a potent and selective heterobifunctional degrader of EP300 with biological activity in hematological malignancy. We observed that selective degradation of EP300 has anti-proliferative activity in a broad range of hematological malignancies in vitro, including diffuse large B-cell lymphoma, multiple myeloma, and follicular lymphoma. We also achieved in vivo efficacy in a Karpas422 GCB-DLBCL xenograft model. Importantly, an investigational safety study was performed in mice at efficacious doses, and no thrombocytopenia was observed. Therefore, leveraging targeted protein degradation to achieve selective EP300 degradation shows promise to be a well-tolerated and effective treatment strategy for advanced hematological malignancies. Citation Format: Claudia Dominici, Qianhe Zhou, Laura La Bonte, Mark Zimmerman, Mei Yun Lin, Wesley Austin. Anti-cancer activity of potent and selective EP300 degradation in hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7186.