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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–proteinmore » interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.« less

Authors:
; ; ; ; ; ; ; ;  [1];  [2]
  1. Michigan
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHER
OSTI Identifier:
1061311
Resource Type:
Journal Article
Journal Name:
Journal of the American Chemical Society (Online)
Additional Journal Information:
Journal Volume: 135; Journal Issue: 2; Journal ID: ISSN 1520-5126
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Karatas, Hacer, Townsend, Elizabeth C, Cao, Fang, Chen, Yong, Bernard, Denzil, Liu, Liu, Lei, Ming, Dou, Yali, Wang, Shaomeng, and HHMI). High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction. United States: N. p., 2013. Web. doi:10.1021/ja306028q.
Karatas, Hacer, Townsend, Elizabeth C, Cao, Fang, Chen, Yong, Bernard, Denzil, Liu, Liu, Lei, Ming, Dou, Yali, Wang, Shaomeng, & HHMI). High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction. United States. doi:10.1021/ja306028q.
Karatas, Hacer, Townsend, Elizabeth C, Cao, Fang, Chen, Yong, Bernard, Denzil, Liu, Liu, Lei, Ming, Dou, Yali, Wang, Shaomeng, and HHMI). Tue . "High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction". United States. doi:10.1021/ja306028q.
@article{osti_1061311,
title = {High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction},
author = {Karatas, Hacer and Townsend, Elizabeth C and Cao, Fang and Chen, Yong and Bernard, Denzil and Liu, Liu and Lei, Ming and Dou, Yali and Wang, Shaomeng and HHMI)},
abstractNote = {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.},
doi = {10.1021/ja306028q},
journal = {Journal of the American Chemical Society (Online)},
issn = {1520-5126},
number = 2,
volume = 135,
place = {United States},
year = {2013},
month = {2}
}