Catalytic Inhibition of p300 Preferentially Targets IRF4 Oncogenic Activity and Tumor Growth in Multiple Myeloma

The oncogenic transcription factor (TF) IRF4 is a currently undrugged universal multiple myeloma dependency. Using transcriptional regulatory network mapping, an unbiased multiomics target ID approach, we identified the coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. Validation of this preferential relationship through quantitative interactome mapping revealed that IRF4 was the most abundant multiple myeloma-specific dependency and more closely complexed with p300 than other TFs, such as IKZF1/IKZF3. Development of optimized p300 KAT inhibitors enabled inhibition of IRF4 activity and multiple myeloma proliferation ex vivo and in vivo. p300/CBP KAT inhibition preferentially targeted multiple myeloma cells over normal cells, specifically modulating the multiple myeloma transcriptome, and the p300 KAT inhibitors more completely inhibited IRF4 activity at lower levels compared with existing p300/CREB-binding protein (CBP) bromodomain inhibitors. Furthermore, combining p300/CBP KAT inhibition and therapeutics with orthogonal mechanisms targeting transcription in multiple myeloma elicited synergistic antitumor effects. Together, these data motivate the ongoing clinical development of p300/CBP KAT inhibition in multiple myeloma. SIGNIFICANCE: Inhibition of p300 lysine acetyltransferase activity preferentially modulates the IRF4 transcriptional regulatory network and is orthogonal to mechanisms of multiple myeloma standard-of-care treatment, supporting the translational potential of p300 inhibitors.