Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer

J Med Chem. 2023 Dec 14;66(23):16168-16186. doi: 10.1021/acs.jmedchem.3c01521. Epub 2023 Nov 29.


As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic cancer and several potentially useful tool compounds.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Mice
  • Pancreatic Neoplasms* / drug therapy
  • Proteolysis
  • Proteolysis Targeting Chimera*
  • Structure-Activity Relationship
  • Ubiquitin-Protein Ligases / metabolism


  • Proteolysis Targeting Chimera
  • Ubiquitin-Protein Ligases