Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9

SLAS Discov. 2019 Feb;24(2):133-141. doi: 10.1177/2472555218809904. Epub 2018 Oct 25.


Eleven-nineteen leukemia (ENL) contains an epigenetic reader domain (YEATS domain) that recognizes lysine acylation on histone 3 and facilitates transcription initiation and elongation through its interactions with the super elongation complex (SEC) and the histone methyl transferase DOT1L. Although it has been known for its role as a fusion protein in mixed lineage leukemia (MLL), overexpression of native ENL, and thus dysregulation of downstream genes in acute myeloid leukemia (AML), has recently been implicated as a driver of disease that is reliant on the epigenetic reader activity of the YEATS domain. We developed a peptide displacement assay (histone 3 tail with acylated lysine) and screened a small-molecule library totaling more than 24,000 compounds for their propensity to disrupt the YEATS domain-histone peptide binding. Among these, we identified a first-in-class dual inhibitor of ENL ( Kd = 745 ± 45 nM) and its paralog AF9 ( Kd = 523 ± 53 nM) and performed "SAR by catalog" with the aim of starting the development of a chemical probe for ENL.

Keywords: AF9; ENL; MLLT1; MLLT3; YEATS domain; small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biophysical Phenomena
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Peptides / metabolism
  • Protein Domains
  • Structure-Activity Relationship
  • Transcriptional Elongation Factors / antagonists & inhibitors*
  • Transcriptional Elongation Factors / chemistry*


  • Histones
  • Peptides
  • Transcriptional Elongation Factors