Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

J Med Chem. 2018 Jul 12;61(13):5623-5642. doi: 10.1021/acs.jmedchem.8b00375. Epub 2018 Jun 29.


WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / chemistry*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Intracellular Signaling Peptides and Proteins
  • Structure-Activity Relationship


  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • WDR5 protein, human
  • Histone-Lysine N-Methyltransferase