On the basis of a previously identified
DOT1L peptide mimetic (compound 3), a series of novel
peptide mimetics were designed and synthesized.
These compounds can potently bind to AF9 and ENL either in cell-free
binding assays or in leukemia cells, and selectively inhibit the growth
of leukemia cells containing mixed lineage leukemia (MLL) fusion proteins.
The most potent compound 12 exhibited comparable anticancer
cellular activities to those of EPZ5676, a clinical stage enzymatic
inhibitor of DOT1L in several leukemia cell lines containing MLL fusion
proteins. Mechanism studies for compound 12 indicated
that it did not affect the global methylation of H3K79 catalyzed by
DOT1L but could effectively suppress the methylation of H3K79 at MLL
fusion proteins targeted genes and inhibit the expressions of these
genes. Our studies thus demonstrated that inhibiting the protein–protein
interactions between DOT1L and MLL fusion proteins is a potentially
effective strategy for the treatment of MLL rearranged
leukemias.
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