Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.

ABSTRACT: Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC₅₀ = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compati

SUBMITTER: Garnar-Wortzel L 

PROVIDER: S-EPMC8161486 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature