4OG5: Human Menin With Bound Inhibitor Miv-5

Citation:
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 approximately 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.
PDB ID: 4OG5Download
MMDB ID: 118102
PDB Deposition Date: 2014/1/15
Updated in MMDB: 2014/03 
Experimental Method:
x-ray diffraction
Resolution: 1.63  Å
Source Organism:
Similar Structures:
Biological Unit for 4OG5: monomeric; determined by author and by software (PISA)
Molecular Components in 4OG5
Label Count Molecule
Protein (1 molecule)
1
Menin
Molecule annotation
Chemicals (9 molecules)
1
1
2
2
3
1
4
1
5
3
6
1
* Click molecule labels to explore molecular sequence information.

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