1. Academic Validation
  2. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction

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.
Hacer Karatas 1 Elizabeth C Townsend Fang Cao Yong Chen Denzil Bernard Liu Liu Ming Lei Yali Dou Shaomeng Wang
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
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.

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