Discovery of a paralog selective p300 protein degrader with potent anti-cancer activity in hematological malignancies

The E1A-associated protein p300 (EP300) functions as a key regulator of oncogenic transcriptional programs, positioning it as an attractive therapeutic target in cancer. However, the high sequence homology between p300 and its paralog CREB-binding protein (CBP) has limited the development of selective inhibitors, often resulting in dose-limiting toxicities. In this study, we report the discovery of a highly potent and selective degrader of p300. Distinct from dual p300/CBP degraders, this compound exhibits enhanced formation and stability of the ternary complex with p300, drives stronger ubiquitination and proteasomal recruitment, and targets a unique lysine residue on p300 for degradation. Hematological malignancies including multiple myeloma, non-Hodgkin's lymphoma, and acute myeloid leukemia were particularly sensitive to p300-selective degradation, which elicited a cytotoxic response in cancer cells and demonstrated robust antitumor activity in xenograft models. Together, these findings establish selective p300 degradation as a promising therapeutic approach for hematologic cancers and a novel strategy to disrupt oncogenic transcriptional dependencies. All Authors were or are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. No honoraria or payments were made for authorship.