A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-directed Cell Death [CUT&RUN]

Lysine acetyltransferases (KATs) such as p300 and CBP regulate gene networks in healthy and malignant cells by scaffolding transcriptional machinery and by acetylating chromatin and transcription factors (TFs). In certain cancers including diffuse large B cell lymphomas, they contribute to tumor suppression and are therapeutic vulnerabilities when deregulated. Inhibitors and degraders of KATs are limited by potential toxicity associated with targeting these essential proteins. We introduce KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity), bivalent molecules that redirect the KAT and co-activating activity of p300 and CBP towards programmed cell death signaling repressed by the oncogenic TF BCL6. The lead KAT-TCIP molecule kills lymphoma cells at ~0.8 nM by redistributing chromatin acetylation, activating the pro-apoptotic protein PUMA, and repressing c-MYC. Analysis of the ternary co-crystal structure containing p300 and BCL6 reveals fortuitous interactions that drive the potency and specificity of KAT-TCIPs and sets a precedent for KAT-targeting induced proximity therapeutics.