Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain.
Xinyu R MaLongxia XuShiqing XuBrianna J KleinHongkuan WangSukant DasKuai LiKai S YangSana SohailAndrew ChapmanTatiana G KutateladzeXiaobing ShiWenshe Ray LiuHong WenPublished in: Journal of medicinal chemistry (2021)
Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.
Keyphrases
- small molecule
- acute myeloid leukemia
- protein protein
- induced apoptosis
- bone marrow
- endothelial cells
- cell cycle arrest
- structure activity relationship
- dna methylation
- endoplasmic reticulum stress
- intensive care unit
- signaling pathway
- cell death
- extracorporeal membrane oxygenation
- respiratory failure
- fluorescence imaging
- cell proliferation
- binding protein
- single cell
- acute respiratory distress syndrome
- hepatitis b virus
- induced pluripotent stem cells
- nucleic acid
- fluorescent probe