Paralogue-specific degradation of the histone acetyltransferase EP300

Authors

• JH Williams
• M Crawford
• D Tripu
• Y Xiong
• X Chen
• A Shaik
• S Barrit
• Y Jing
• D Gallimore
• S Kales
• N Bhanu
• Y Fang
• K Butler
• C LeClair
• N Coussens
• A Simeonov
• B Garcia
• R Swenson
• C Dibble
• JL Meier

Abstract

An emerging topic of oncology is the prevalence of lysine acetylation in post-translational
modification (PTM). This process could provide a selective route for targeting oncogenic transcription
therapeutically. Specifically, EP300 and CREBBP are human enzymes involved in catalyzing acetylation.
These multidomain protein paralogues, commonly denoted as EP300/CREBBP, exhibit highly similar
acetyltransferase active sites, sharing over 95% identity. Since dual knockout of EP300/CREBBP is lethal
in mammals, it has been hypothesized that to be effective a therapeutic it would be optimal to develop
paralogue-specific inhibitors of these enzymes. However, a major question is how to differentiate them
based on their high similarity. Here we report a targeted protein degradation (TPD) approach to paraloguespecific
inhibition of EP300.

Scientific Focus Area: Chemical Biology

This page was last updated on Tuesday, August 6, 2024