Acute myeloid leukemia (AML) is the second most diagnosed and the deadliest subtype of leukemia. Recently genetic loss-of-function studies have demonstrated that a human YEATS domain-containing protein named eleven-nineteen-leukaemia (ENL) functions as a transcriptional coactivator and is essential for the proliferation of AML that harbour oncogenic multiple lineage leukemia (MLL) rearrangements. Our previous studies have demonstrated a series of ENL inhibitors (1, 7-15 and 24) displaying significant and specific inhibitory effects targeting ENL YEAST domain. In this study, we developed a NanoBRET system which allows the analysis of cellular permeability, potency, selectivity, and stability of synthesized ENL inhibitors. Followed by in vitro metabolic stability and cell growth inhibition studies, we identified a potent and specific ENL YEATS domain inhibitor 13 with both high in vitro metabolic stability and strong anti-proliferation ability on MLL-fusion leukemia cell lines. Cumulatively, this study established 13 as a promising inhibitor to disrupt the pathogenic functions of ENL for acute myeloid leukemia treatment.

Development of small molecule inhibitors selectively targeting the ENL YEATS domain for treating acute myeloid leukemia

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.