High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction

• DOI: 10.1021/ja306028q
• Publication Date: 2012-12-05T14:21:04Z
• Authors: Hacer Karatas; Elizabeth C. Town...; Fang Cao; Yong Chen; Denzil Bernard; Liu Liu; Ming Lei; Yali Dou; Shaomeng Wang
• Keywords: Peptidomimetic

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