High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction
| Autor: | Denzil Bernard, Fang Cao, Ming Lei, Elizabeth C. Townsend, Liu Liu, Yong Chen, Shaomeng Wang, Yali Dou, Hacer Karatas |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Histone H3 Lysine 4 Methyltransferase Peptidomimetic Biochemistry Binding Competitive Models Biological Catalysis Article Protein–protein interaction Small Molecule Libraries Colloid and Surface Chemistry Drug Delivery Systems Humans chemistry.chemical_classification Intracellular Signaling Peptides and Proteins General Chemistry Histone-Lysine N-Methyltransferase Small molecule Fusion protein In vitro Enzyme chemistry Peptidomimetics Myeloid-Lymphoid Leukemia Protein Protein Binding |
| Zdroj: | Journal of the American Chemical Society. 135(2) |
| ISSN: | 1520-5126 |
| Popis: | 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 Ki < 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. |
| Databáze: | OpenAIRE |
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