An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma [SLAM-seq]

Chemical inhibition of these multidomain factors, either through the bromodomain or the catalytic acetyltransferase domain, show promising activity in pre-clinical models of myeloma and other cancers. Some compounds, including the CBP/p300 bromodomain inhibitor inobrodib, have progressed to early-stage clinical trials.

Chemical degradation of CBP/p300 is the only modality that can completely disrupt all functional domains of CBP and p300. Our previous attempts to induce CBP/p300 targeted degradation led to dCBP-1, a potent tool compound that induces degradation of both CBP and p300 by hijacking the activity of the E3 ligase CRBN. Here we comprehensively demonstrate across a large panel of cell lines how CBP/p300 degradation compares to inhibition, with pronounced selective antiproliferative activity towards multiple myeloma cells.