Article

Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

Department of Pathology, University of Michigan, Ann Arbor, MI, United States
Blood (Impact Factor: 10.43). 08/2012; 120(23). DOI: 10.1182/blood-2012-05-429274
Source: PubMed

ABSTRACT Menin functions as a critical oncogenic co-factor of Mixed Lineage Leukemia (MLL) fusion proteins in development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving two N-terminal fragments of MLL. Here, we report the first high resolution crystal structure of human menin in complex with a small molecule inhibitor of the menin-MLL interaction, MI-2. The structure reveals that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22 nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, downregulation of Hoxa9 expression and differentiation. Together, our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small molecule inhibitor.

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