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

  • SLAS Discov. 2019 Feb;24(2):133-141. doi: 10.1177/2472555218809904.
Thomas Christott  1 ,  James Bennett  1 ,  Carmen Coxon  1 ,  Octovia Monteiro  1 ,  Charline Giroud  1 ,  Viktor Beke  1 ,  Suet Ling Felce  2 ,  Vicki Gamble  2 ,  Carina Gileadi  2 ,  Gennady Poda  3  4 ,  Rima Al-Awar  3  5 ,  Gillian Farnie  2 ,  Oleg Fedorov  1
Affiliations
  • 1. 1 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
  • 2. 2 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Botnar Research Centre, Oxford, UK.
  • 3. 3 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 4. 4 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
  • 5. 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
PMID: 30359161 DOI: 10.1177/2472555218809904
Abstract

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.
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