Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

J Med Chem. 2021 Aug 12;64(15):10682-10710. doi: 10.1021/acs.jmedchem.1c00146. Epub 2021 May 13.


Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Cells, Cultured
  • Dihydropyridines / chemical synthesis
  • Dihydropyridines / chemistry
  • Dihydropyridines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Male
  • Molecular Structure
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Biphenyl Compounds
  • Dihydropyridines
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • OICR-9429
  • WDR5 protein, human