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SLAS Discov. 2018 Oct 25:2472555218809904. doi: 10.1177/2472555218809904. [Epub ahead of print]

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

Author information

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.

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

PMID:
30359161
DOI:
10.1177/2472555218809904

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