2. Academic Validation
  3. Targeted degradation of the enhancer lysine acetyltransferases CBP and p300

Targeted degradation of the enhancer lysine acetyltransferases CBP and p300

  • Cell Chem Biol. 2021 Apr 15;28(4):503-514.e12. doi: 10.1016/j.chembiol.2020.12.004.
Raghu Vannam 1,  Jan Sayilgan 2,  Samuel Ojeda 2,  Barbara Karakyriakou 2,  Eileen Hu 2,  Johannes Kreuzer 1,  Robert Morris 1,  Xcanda Ixchel Herrera Lopez 2,  Sumit Rai 1,  Wilhelm Haas 1,  Michael Lawrence 3,  Christopher J Ott 4
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • 3 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA.
  • 4 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.ott@mgh.harvard.edu.
PMID: 33400925 DOI: 10.1016/j.chembiol.2020.12.004
Abstract

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.

Keywords

CBP; HAT; KAT; PROTAC; enhancer; histone acetyltransferase; lysine acetyltransferase; multiple myeloma; p300.

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