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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301413 | GEO | 2026/02/26

REPOSITORIES: GEO

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Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.

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

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