High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction

J Am Chem Soc. 2013 Jan 16;135(2):669-82. doi: 10.1021/ja306028q. Epub 2012 Dec 27.


Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Drug Delivery Systems*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / drug effects
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Models, Biological
  • Models, Molecular
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
  • Myeloid-Lymphoid Leukemia Protein / drug effects
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Peptidomimetics* / chemistry
  • Protein Binding / drug effects
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology


  • Intracellular Signaling Peptides and Proteins
  • Peptidomimetics
  • Small Molecule Libraries
  • WDR5 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase