Development of DOT1L-Targeted Protein Degraders for Treating MLL-r Leukemia
Songhua Quan1,2, Kenji Unno1,2, Dikshat G Gupta1,2
1Department of Urology, Northwestern University Feinberg School of Medicine; Chicago, Illinois 60611, United States.
Abstract:
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.
Insights
New proteolysis-targeting chimeras (PROTACs) effectively degrade DOT1L, a key driver in MLL-rearranged leukemias. This protein degradation approach shows promise for treating resistant leukemia forms.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- DOT1L is a critical oncogenic driver in MLL-rearranged (MLL-r) leukemias.
- Existing catalytic inhibitors have shown limited clinical efficacy.
- Nonenzymatic functions of DOT1L are crucial for leukemia progression.
Purpose of the Study:
- To develop novel DOT1L-targeting PROTACs to degrade DOT1L and inhibit its functions.
- To evaluate the efficacy of these PROTACs in MLL-r leukemia models.
Main Methods:
- Development and characterization of DOT1L-targeting PROTACs (DOT1L705 and DOT1L808).
- Assessment of PROTACs' potency and selectivity.
- Evaluation of DOT1L705's effect on leukemia cell viability, including menin inhibitor-resistant cells.
- In vivo studies of DOT1L808 in an orthotopic leukemia model.
Main Results:
- DOT1L705 and DOT1L808 demonstrated potent and selective DOT1L degradation (DC50 values as low as 5 nM).
- DOT1L705 showed efficacy dependent on MLL-r status and retained activity against resistant cells.
- DOT1L808 achieved complete tumor regression in vivo without significant toxicity.
Conclusions:
- Protein degradation via PROTACs is a viable therapeutic strategy for MLL-r leukemias.
- DOT1L-targeting PROTACs offer a promising approach to overcome limitations of current therapies.
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