High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction.
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.
Department of Pathology, University of Michigan , Ann Arbor, 1150 West Medical Center Drive, MSRBI, Room 4510D, Michigan, 48109, United States.
Shihan
S
He
Timothy J
TJ
Senter
Jonathan
J
Pollock
Changho
C
Han
Sunil Kumar
SK
Upadhyay
Trupta
T
Purohit
Rocco D
RD
Gogliotti
Craig W
CW
Lindsley
Tomasz
T
Cierpicki
Shaun R
SR
Stauffer
Jolanta
J
Grembecka
D002151:Calorimetry; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D054852:Small Molecule Libraries; D021241:Spectrometry, Mass, Electrospray Ionization
D010880:Piperidines; D054852:Small Molecule Libraries; D051788:Myeloid-Lymphoid Leukemia Protein