Abstract IA001: Targeting chromatin modulators with therapeutic degraders

Abstract E1A binding protein (EP300) is a histone acetyltransferase, which modifies chromatin and drives the expression of oncogenes critical in several hematological malignancies and solid tumors. Current pharmacological inhibitors targeting EP300 are not very selective and result in adverse effects, such as thrombocytopenia. Therefore, the development of agents that selectively target EP300 is of high interest as it has the potential to broaden the therapeutic window. Using the targeted degradation approach, we have developed a potent and selective heterobifunctional degrader of EP300 with biological activity in multiple hematological malignancies, including diffuse large B-cell lymphoma, multiple myeloma, and follicular lymphoma. We observed excellent translation of in vitro sensitivities to profound efficacies in a series of xenograft-based in vivo studies. Importantly, an investigational safety study was performed in mice at efficacious doses, and no thrombocytopenia was observed. To further investigate the therapeutic potential of this novel class of agents, we also demonstrated synergistic effects of EP300 degraders with several standard-of-care agents (such as IMiDs, dexamethasone, and venetoclax) in several tumor indications. Collectively, leveraging targeted protein degradation to achieve selective EP300 degradation shows promise to be a well-tolerated and effective treatment strategy for multiple hematological malignancies. Citation Format: Gromek Smolen. Targeting chromatin modulators with therapeutic degraders [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr IA001.