Related Experiment Video

Updated: Jan 1, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a

Jianhua Tian, Kevin B Teuscher, Erin R Aho

  • 1Leidos Biomedical Research , Frederick National Laboratory for Cancer Research , Frederick , Maryland 21701 , United States.

Journal of Medicinal Chemistry
|December 21, 2019
PubMed

Insights

Researchers discovered novel compounds that inhibit WD repeat domain 5 (WDR5) by targeting its WIN site. These WDR5 inhibitors show promise for treating cancers, particularly those driven by MYC.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • WD repeat domain 5 (WDR5) is crucial for chromatin regulation and its overexpression is linked to poor cancer prognosis.
  • WDR5 is a therapeutic target, with drug discovery efforts focusing on its WIN site for chromatin recruitment inhibition.

Purpose of the Study:

  • To discover novel antagonists targeting the WDR5 WIN site.
  • To evaluate the therapeutic potential of these novel WDR5 inhibitors in cancer models.

Main Methods:

  • Structure-based drug design was employed to identify compounds with a dihydroisoquinolinone bicyclic core.
  • Binding affinity, antiproliferative activity in MLL-fusion and MYC-driven cancer cell lines, and effects on MYC recruitment were assessed.

Main Results:

  • Novel WDR5 WIN site antagonists with picomolar binding affinity were discovered.
  • These compounds demonstrated selective, concentration-dependent antiproliferative effects in sensitive cancer cell lines.
  • Inhibition of MYC-driven cancer cell proliferation and reduced MYC recruitment to chromatin were observed.

Conclusions:

  • The identified WDR5 WIN site binders represent a promising starting point for developing anti-WDR5 therapeutics.
  • These molecules serve as valuable tools for investigating WDR5's role in cancer progression and therapeutic inhibition.

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