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

A Shi, MJ Murai, S He, G Lund, T Hartley… - Blood, The Journal …, 2012 - ashpublications.org
A Shi, MJ Murai, S He, G Lund, T Hartley, T Purohit, G Reddy, M Chruszcz, J Grembecka…
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion
proteins in the 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 2 N-terminal fragments of MLL. In the
present study, we reveal 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 shows that …
Abstract
Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the 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 2 N-terminal fragments of MLL. In the present study, we reveal 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 shows 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 (Kd = 22nM) 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, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of 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.
ashpublications.org