Targeted degradation of the enhancer lysine acetyltransferases CBP and p300

The chromatin regulators CBP and p300 maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. We have developed a chemical degrader of p300/CBP, dCBP-1, using in silico modeling and cellular activity assays including capillary-based immunodetection assays (ProteinSimple, WES). We have found that dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drive MYC oncogene expression. As an efficient degrader of this unique class of chromatin regulators, dCBP-1 will be a useful tool for understanding p300/CBP activity at enhancers in both normal and diseased cells.