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, high sequence similarity to its paralog, CREB-binding protein (CBP), has hindered the development of selective inhibitors, leading to toxic side effects. Here, we describe a highly potent and selective p300 degrader. Unlike dual p300/CBP degraders, this compound forms a stronger, more stable ternary complex with p300, induces higher level of p300 ubiquitination and recruitment to the proteosome, and ubiquitinates a unique lysine site on p300. Hematological cancers, including multiple myeloma, non-Hodgkin's lymphoma and acute myeloid leukemia, showed the greatest sensitivity to the p300-selective degrader, which induced a lethal phenotype in cells and demonstrated antitumor efficacy in xenograft models. These findings highlight the therapeutic potential of selective p300 degradation as a novel strategy for the treatment of hematological malignancies and the inhibition of cancer progression. Overall design: RNAseq profiling in NCI-H929 cells 1) treated with p300 degrader 27 at 3 nM for 6 hours when compared with DMSO as vehicle and 2) p300 knockout when compared with NTC