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

The E1A-associated protein p300 (EP300) is a key regulator of oncogenic transcription factors, making it a promising target for cancer therapy. However, its high sequence similarity to its paralog, CREB-binding protein (CBP), has hindered the development of selective inhibitors, leading to dose-limiting toxicities. Here, we describe the discovery of a highly potent and selective p300 degrader. Unlike dual p300/CBP degraders, this compound forms a more stable ternary complex with p300, driving enhanced proteasomal recruitment and ubiquitination. Notably, our data uncover a previously unrecognized mechanism of paralog selectivity mediated by regioselective ubiquitination of a unique lysine residue on p300. Hematological malignancies, including multiple myeloma, non-Hodgkin lymphoma, and acute myeloid leukemia, exhibit marked sensitivity to selective p300 degradation, resulting in cell lethality and robust antitumor activity in xenograft models. These findings establish selective p300 degradation as a mechanistically distinct and promising therapeutic strategy in hematological malignancies.