1560968-58-2Relevant academic research and scientific papers
MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF
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, (2015/01/09)
The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperdine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.
MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF
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, (2015/01/06)
The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperidine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.
High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction
He, Shihan,Senter, Timothy J.,Pollock, Jonathan,Han, Changho,Upadhyay, Sunil Kumar,Purohit, Trupta,Gogliotti, Rocco D.,Lindsley, Craig W.,Cierpicki, Tomasz,Stauffer, Shaun R.,Grembecka, Jolanta
, p. 1543 - 1556 (2014/03/21)
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.
