Targeted degradation of the enhancer lysine acetyltransferases CBP and p300

The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. Small molecule inhibitors that target some of these domains have been developed; however, they cannot completely ablate p300/CBP function in cells. Here we describe a chemical degrader of p300/CBP, dCBP-1. Leveraging structures of ligand-bound p300/CBP domains, we use in silicomodeling of ternary complex formation with the E3 ubiquitin ligase cereblon to enable degrader design. dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drives MYC oncogene expression. As an efficient degrader of this unique class of acetyltransferases, dCBP-1 is a useful tool alongside domain inhibitors for dissecting the mechanism by which these factors coordinate enhancer activity in normal and diseased cells.

Automated summary

The study presents a chemical degrader of p300/CBP, dCBP-1, designed by leveraging structures of ligand-bound p300/CBP through in silico modeling of ternary complex formation. It is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer driving oncogene expression. This efficient degrader provides a useful tool for dissecting the mechanism by which these factors coordinate enhancer activity in normal and diseased cells, alongside domain inhibitors.