2. Academic Validation
  3. Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9

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

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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