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Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5

Guillermo Senisterra1, Hong Wu, Abdellah Allali-Hassani

  • 1Structural Genomics Consortium, 101 College Street, Toronto, Ontario, Canada.

The Biochemical Journal
|September 20, 2012
PubMed

Insights

Researchers developed a small molecule to block the interaction between WD40 repeat protein 5 (WDR5) and mixed-lineage leukemia protein (MLL). This WDR5-MLL inhibitor shows potential for treating cancers like MLL-rearranged leukemias.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • WD40 repeat protein 5 (WDR5) is a key component of SET1/mixed-lineage leukemia (MLL) complexes.
  • These complexes are crucial for histone 3 Lys4 trimethylation (H3K4me3), impacting development and cancer.
  • Aberrant WDR5 expression is linked to various malignancies.

Purpose of the Study:

  • To investigate the potential of small molecules to antagonize the WDR5-MLL interaction.
  • To characterize the binding and inhibitory mechanism of a novel small molecule antagonist.
  • To explore therapeutic strategies for WDR5-dependent cancers.

Main Methods:

  • Small molecule screening and synthesis.
  • Structural and biophysical analyses (e.g., binding affinity determination).
  • In vitro enzymatic assays to assess MLL core complex activity.

Main Results:

  • A small molecule antagonist was identified that binds to the WDR5 peptide-binding pocket with a Kd of 450 nM.
  • The antagonist inhibits the catalytic activity of the MLL core complex in vitro.
  • Inhibition efficacy was concentration-dependent, suggesting WDR5 stabilizes the MLL complex.

Conclusions:

  • The study demonstrates successful inhibition of a critical protein-protein interaction involving WDR5 and MLL.
  • This provides a foundation for developing targeted therapies against WDR5-dependent enzymes.
  • Potential applications include treatment of MLL-rearranged leukemias and other cancers.

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