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Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction

Jian Ding1, Guo Li2, Hejun Liu2,3

  • 1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts02139, United States.

ACS Chemical Biology
|January 3, 2023
PubMed

Insights

Researchers discovered new WDR5 inhibitors targeting a novel pocket, distinct from the WIN site. These compounds disrupt WDR5-MYC interactions, offering new therapeutic strategies for cancer and neurodegenerative diseases.

Area of Science:

  • Molecular Biology
  • Drug Discovery
  • Biochemistry

Background:

  • WD repeat domain 5 (WDR5) is a crucial protein in the WD40-repeat family, implicated in cancer, aging, and neurodegenerative disorders.
  • WDR5's function relies on interactions with various partners, with current drug discovery focusing on the WIN (WDR5 interaction motif) site.
  • Targeting WDR5 offers therapeutic potential, but novel inhibition strategies are needed.

Purpose of the Study:

  • To discover novel WDR5 inhibitors targeting the WDR5 binding motif (WBM) pocket.
  • To disrupt the interaction between WDR5 and its binding partner MYC.
  • To develop new chemical probes and therapeutic strategies for WDR5-related diseases.

Main Methods:

  • High-throughput biochemical screening to identify WDR5 inhibitors.
  • Subsequent molecule optimization to enhance inhibitor properties.
  • Biological assessment to validate inhibitor efficacy and mechanism.

Main Results:

  • Discovery of novel small molecules targeting the WBM pocket of WDR5.
  • Demonstration that these inhibitors disrupt WDR5-MYC interactions.
  • Validation of these compounds as useful probes for WDR5 research.

Conclusions:

  • Novel WDR5 inhibitors targeting the WBM pocket have been identified.
  • These inhibitors offer a new avenue for therapeutic intervention beyond the WIN site.
  • The discovered compounds serve as valuable tools for further WDR5 research and drug development.

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