1. Targeted degradation of the enhancer lysine acetyltransferases CBP and p300
Jan Sayilgan,Robert Morris,Samuel Ojeda,Johannes Kreuzer,Michael Lawrence,Sumit Rai,Xcanda Ixchel Herrera Lopez,Eileen Hu,Barbara Karakyriakou,Raghu Vannam,Christopher J Ott,Wilhelm Haas Cell Chem Biol . 2021 Apr 15;28(4):503-514.e12. doi: 10.1016/j.chembiol.2020.12.004.
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 silico modeling 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.
2. Chemical control of multidomain acetyltransferase activity
Jordan L Meier,Yihang Jing,Whitney K Lieberman Cell Chem Biol . 2021 Apr 15;28(4):433-435. doi: 10.1016/j.chembiol.2021.03.015.
Chromatin-modifying lysine acetyltransferases employ multiple protein domains to regulate transcription. In this issue, Vannam et al. (2021) describe dCBP-1, a small molecule degrader of the multidomain acetyltransferases EP300 and CREBBP. This provides a new tool for interrogating EP300/CREBBP function and also suggests a strategy for pharmacological differentiation of acetyltransferase paralogs.
