GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301413/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301413GEOGSEfalseDiscovery of a paralog-selective p300 protein degrader with potent anti-cancer activity in hematological malignanciesThe 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.2026/02/26GSE301413GSM9082751GSM9082750GSM9082753GSM9082752GSM9082755GSM9082754GSM9082748GSM9082749GSM9396779GSM9396786GSM9396785GSM9396784GSM9396783GSM9396782GSM9396781GSM939678020301301413Homo sapiens