| MLL1 is a histone-3 lysine-4 (H3K4) methyltransferase, which is misregulated in patients with leukemia and linked with tumorigenicity through upregulation of the target genes HoxA9 and Meis-1. Suppressing expression of these genes by targeting the catalytic activity of MLL1 may be a novel approach in cancer therapy. Methylation of H3K4 by MLL1 requires formation of a core complex consisting of MLL1, WDR5, RbBPS and ASH2L. The interaction between MLL1 and WDR5 in this complex is essential for its catalytic activity and disruption of the MLL1-WDR5 interaction may provide significant therapeutic benefit to suppress target gene expression and thus tumorigenesis.;In this study, the design of peptidomimetic inhibitors that can disrupt the interaction between MLL1 and WDR5 is presented. Starting from a 12mer peptide, the tripeptide -CO-ARA-NH- in MLL1 was identified as the minimal motif for binding to WDR5. Systematic modifications to the Ac-ARA-NH 2 tripeptide were performed to elucidate the interaction of WDR5 with its ligands, and a number of peptidomimetic compounds with K i < 1 nM for WDR5 were developed. These compounds were also demonstrated to effectively inhibit the catalytic activity of the reconstituted MLL1 core complex in vitro. Further modifications to improve cellular permeability of the peptidomimetic inhibitors led to design of MM-101 and MM-102, which have subnanomolar binding affinities for WDR5. Crystal structures of MM-101 and MM-102 provide insight for further development of inhibitors. MM-102 inhibits the interaction between MLL1 and WDR5 in vitro, and reduces expression of HoxA9 and Meis-1 genes in MLL1-AF9 transduced bone marrow cells. These findings, together with the selective growth inhibition of leukemia cell lines with MLL1 fusion proteins upon treatment with MM-102, suggest that inhibitors targeting the MLL1-WDR5 interaction have a therapeutic potential in cancer therapy. |
