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

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.