Development of DOT1L-Targeted Protein Degraders for Treating MLL‑r Leukemia

DOT1L is aberrantly
recruited in MLL-r leukemias and
serves as
a critical oncogenic driver. Substantial previous work has developed
catalytic inhibitors like pinometostat, which showed limited clinical
efficacy. Recent work has defined nonenzymatic functions of DOT1L
in promoting leukemia progression. Because these functions cannot
be blocked by enzymatic inhibitors, we developed novel DOT1L-targeting
PROTACs (Proteolysis-Targeting Chimeras ) to degrade the protein and
thereby block all of its functions. We describe PROTACs DOT1L705 and
DOT1L808 as potent and highly selective DOT1L degraders with DC50 values of 0.33 μM and 5 nM, respectively. The effect
of DOT1L705 on cell viability is highly dependent on the MLL-r status
of leukemia cell lines, and it retains activity against menin inhibitor-resistant
cells. In vivo studies with DOT1L808 showed its ability to achieve
complete tumor regression in an orthotopic leukemia model without
overt toxicity. These results establish protein degradation as a promising
therapeutic strategy for MLL-rearranged leukemias.