Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia

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 compatible with cell-based
drug discovery. Through these efforts, we discovered SR-0813, a potent
and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25
nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114,
we detailed the biological response of AML cells to pharmacological
ENL disruption for the first time. Most notably, we discovered that
ENL YEATS inhibition is sufficient to selectively suppress ENL target
genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively,
our study establishes YEATS domain inhibition as a viable approach
to disrupt the pathogenic function of ENL in acute leukemia and provides
the first thoroughly characterized chemical probe for the ENL YEATS
domain.