 |
PDBsum entry 4og5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Protein binding/inhibitor
|
PDB id
|
|
|
|
4og5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
High-Affinity small-Molecule inhibitors of the menin-Mixed lineage leukemia (mll) interaction closely mimic a natural protein-Protein interaction.
|
|
|
Authors
|
|
S.He,
T.J.Senter,
J.Pollock,
C.Han,
S.K.Upadhyay,
T.Purohit,
R.D.Gogliotti,
C.W.Lindsley,
T.Cierpicki,
S.R.Stauffer,
J.Grembecka.
|
|
|
Ref.
|
|
J Med Chem, 2014,
57,
1543-1556.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The protein-protein interaction (PPI) between menin and mixed lineage leukemia
(MLL) plays a critical role in acute leukemias, and inhibition of this
interaction represents a new potential therapeutic strategy for MLL leukemias.
We report development of a novel class of small-molecule inhibitors of the
menin-MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which
originated from HTS of ∼288000 small molecules. We determined menin-inhibitor
co-crystal structures and found that these compounds closely mimic all key
interactions of MLL with menin. Extensive crystallography studies combined with
structure-based design were applied for optimization of these compounds,
resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM.
Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia
cells, validating specific mechanism of action. Our studies provide novel and
attractive scaffold as a new potential therapeutic approach for MLL leukemias
and demonstrate an example of PPI amenable to inhibition by small molecules.
|
|
|
|
|
|
|
