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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.

Original publication

DOI

10.1177/2472555218809904

Type

Journal article

Journal

SLAS Discov

Publication Date

02/2019

Volume

24

Pages

133 - 141

Keywords

AF9, ENL, MLLT1, MLLT3, YEATS domain, small-molecule inhibitor, Biophysical Phenomena, Drug Discovery, Drug Evaluation, Preclinical, HEK293 Cells, Histones, Humans, Inhibitory Concentration 50, Peptides, Protein Domains, Structure-Activity Relationship, Transcriptional Elongation Factors