Preclinical evaluation of selective and potent EP300 degraders demonstrates robust antitumor activity and favorable tolerability in hematologic malignancies

E1A binding protein P300 (EP300) is a histone acetyltransferase and transcriptional coactivator that regulates gene expression programs essential for proliferation and survival in hematologic malignancies. Developing selective EP300 agents has been challenging due to the high degree of homology between EP300 and its paralog CREB binding protein (CBP). 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. To address this, we developed heterobifunctional compounds with exquisite selectivity, achieving rapid and sustained EP300 degradation in vivo while sparing CBP. Our previous work demonstrated that selective degradation of EP300 has strong anti-proliferative activity in a broad range of hematologic malignancies in vitro , including diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and follicular lymphoma. In MM.1S xenograft studies, both immediate-release and long-acting injectable formulations of EP300 degraders achieved robust, dose-dependent tumor growth inhibition at well-tolerated exposure levels. Pharmacokinetic and pharmacodynamic analyses revealed a positive correlation between systemic exposure, EP300 degradation, and anti-tumor response. Importantly, selective EP300 degradation in vivo showed minimal impact on body weight and no adverse hematologic effects, such as anemia or thrombocytopenia, in contrast to dual CBP/EP300 inhibitors, indicating a favorable therapeutic window. Collectively, our results establish selective EP300 degradation as a novel and promising therapeutic strategy to treat multiple hematologic malignancies.