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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.

 

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This passage discusses the significance of transcriptional coregulators in regulating gene expression and their potential as targets for controlling tumorigenic gene programs using small molecules. Specifically, it highlights the role of the transcriptional coactivator ENL and its YEATS domain in acute leukemia. The researchers conducted a comprehensive screening of small molecules and identified an inhibitor targeting the ENL YEATS domain, initially with moderate potency (IC50 = 7 μM). Refinement of this inhibitor through a SuFEx-based medicinal chemistry approach led to the development of SR-0813, a more potent and selective inhibitor (IC50 = 25 nM) of the ENL/AF9 YEATS domain.

With SR-0813 and a newly developed ENL PROTAC (SR-1114), the researchers explored the impact of pharmacologically disrupting ENL in acute myeloid leukemia (AML) cells. They found that inhibiting the ENL YEATS domain was effective in selectively suppressing ENL target genes such as HOXA9/10, MYB, MYC, and several other leukemia-related proto-oncogenes. This study establishes YEATS domain inhibition as a promising approach to counter the pathogenic role of ENL in acute leukemia and introduces a well-characterized chemical probe for the ENL YEATS domain, potentially opening avenues for targeted therapies.

Related Products

Cat.No. Product Name Information
E1185 SR-0813 SR-0813 is a potent and selective ENL/AF9 YEATS domain inhibitor. SR-0813 has IC50 values of 25 and 311 nM for ENL YEATS domain and AF9 YEATS domain, respectively.

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