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PDBsum entry 4gm3
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Transcription/transcription inhibitor
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PDB id
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4gm3
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References listed in PDB file
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Key reference
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Title
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High-Affinity, Small-Molecule peptidomimetic inhibitors of mll1/wdr5 protein-Protein interaction.
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Authors
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H.Karatas,
E.C.Townsend,
F.Cao,
Y.Chen,
D.Bernard,
L.Liu,
M.Lei,
Y.Dou,
S.Wang.
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Ref.
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J Am Chem Soc, 2013,
135,
669-682.
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PubMed id
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Abstract
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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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