title: High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hacer
authors.initials: H
authors.lastname: Karatas
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Townsend
authors.forename: Fang
authors.initials: F
authors.lastname: Cao
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D001667:Binding, Competitive; D016503:Drug Delivery Systems; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D057786:Peptidomimetics / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D057786:Peptidomimetics; D054852:Small Molecule Libraries; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase