The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• The WDR5-MLL1 protein-protein interaction is crucial for MLL1's H3K4 methyltransferase activity.
• Dysregulation of MLL1 is implicated in mixed-lineage leukemia, making the WDR5-MLL1 interaction a potential therapeutic target.
• Existing small-molecule inhibitors of this interaction are limited, necessitating the discovery of novel compounds.

Purpose of the Study:

• To discover novel small-molecule inhibitors targeting the WDR5-MLL1 interaction.
• To identify compounds with potent in vitro inhibitory activity against WDR5-MLL1 interaction.
• To explore new scaffolds for developing MLL1-targeting leukemia therapies.

Main Methods:

• High-throughput screening using fluorescence polarization (FP) assays.
• Nuclear Magnetic Resonance (NMR) spectroscopy to confirm direct compound binding to WDR5.
• Similarity-based analog searching and molecular docking studies.

Main Results:

• Several small molecules with potent in vitro inhibitory activity against the WDR5-MLL1 interaction were identified.
• NMR confirmed direct binding of hit compounds to WDR5.
• DC_M5_2 demonstrated the highest inhibitory activity with an IC50 of 9.63 ± 1.46 µM, and docking studies elucidated binding modes.

Conclusions:

• Novel small-molecule inhibitors of the WDR5-MLL1 interaction were successfully discovered through high-throughput screening.
• These compounds, particularly DC_M5_2, represent promising leads for developing new therapeutic strategies against MLL1-driven leukemias.
• Further investigation into these novel scaffolds could advance the development of MLL1 inhibitors for leukemia treatment.