%0 Journal Article
%T Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9
%A Carina Gileadi
%A Carmen Coxon
%A Charline Giroud
%A Gennady Poda
%A Gillian Farnie
%A James Bennett
%A Octovia Monteiro
%A Oleg Fedorov
%A Rima Al-awar
%A Suet Ling Felce
%A Thomas Christott
%A Vicki Gamble
%A Viktor Beke
%J SLAS DISCOVERY: Advancing Life Sciences R&D
%@ 2472-5560
%D 2019
%R 10.1177/2472555218809904
%X 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¨Chistone peptide binding. Among these, we identified a first-in-class dual inhibitor of ENL (Kd = 745 ˇŔ 45 nM) and its paralog AF9 (Kd = 523 ˇŔ 53 nM) and performed ˇ°SAR by catalogˇ± with the aim of starting the development of a chemical probe for ENL
%K YEATS domain
%K MLLT1
%K ENL
%K MLLT3
%K AF9
%K small-molecule inhibitor
%U https://journals.sagepub.com/doi/full/10.1177/2472555218809904