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

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