SR-0813 is a potent and selective inhibitor of the YEATS domain in ENL/AF9, with an IC50 of 25 nM and EC50 of 205 nM for the ENL YEATS domain, and an IC50 of 311 nM and EC50 of 76 nM (CETSA) for the AF9 YEATS domain. It shows over 100-fold lower affinity for MAP3K19 (Kd = 3.5 μM) compared to ENL YEATS (Kd = 30 nM). SR-0813 can be utilized in acute leukemia research.

AF9 YEATS domain:311 nM (IC50), AF9 YEATS domain:76 nM (EC50), ENL YEATS domain:205 nM (EC50), ENL YEATS domain:25 nM (IC50), ENL YEATS domain:30 nM (Kd), MAP3K19:3.5 μM (Kd)

SR-0813, also identified as compound 10, demonstrates a dose-dependent activity in expelling ENL from its known binding sites, including the HOXA10 gene body and MYB promoter within MV4;11 cells at concentrations of 0, 1, and 10 μM over 4 hours. Furthermore, it modulates gene expression in these cells by decreasing the levels of HOXA9, MEIS1, and MYC, while augmenting ITGAM transcript abundance across various time points of 0, 24, 48, and 72 hours at the same concentrations. Notably, at 1 μM for 4 hours, SR-0813 specifically suppresses ENL target genes without broadly altering global gene expression in MV4;11 cells. Over approximately two weeks, SR-0813 shows a marked ability to hinder the proliferation of multiple lineage leukemia (MLL)-fusion leukemia cell lines, including MV4;11, MOLM-13, and OCI/AML-2, in addition to HB11;19 cells, all of which exhibit sensitivity to ENL genetic loss, at concentrations of 0, 1, and 10 μM. This is evidenced in the Cell Proliferation Assay, highlighting SR-0813's potential in targeting MLL-fusion leukemias that harbor ENL dependencies.