1 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK.
2 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Botnar Research Centre, Oxford, UK.
SLAS Discov. 2019 Feb;24(2):133-141. doi: 10.1177/2472555218809904. Epub 2018 Oct 25.
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 ( K = 745 ± 45 nM) and its paralog AF9 ( K = 523 ± 53 nM) and performed "SAR by catalog" with the aim of starting the development of a chemical probe for ENL.
十一号十九号白血病（ENL）包含一个表观遗传读取域（YEATS 域），该域识别组蛋白 3 上赖氨酸的酰化，并通过与超级延伸复合物（SEC）和组蛋白甲基转移酶 DOT1L 的相互作用促进转录起始和延伸。尽管它作为混合谱系白血病（MLL）中的融合蛋白而广为人知，但最近已发现其在急性髓系白血病（AML）中作为一种疾病驱动因子的作用，这依赖于 YEATS 域的表观遗传读取活性。我们开发了一种肽置换测定法（带酰化赖氨酸的组蛋白 3 尾部），并筛选了一个包含超过 24000 种化合物的小分子文库，以确定它们破坏 YEATS 域-组蛋白肽结合的倾向。在这些化合物中，我们鉴定了第一个 ENL（K = 745 ± 45 nM）及其同源物 AF9（K = 523 ± 53 nM）的双抑制剂，并进行了“通过目录进行 SAR”，旨在开发 ENL 的化学探针。
