Complexity of Blocking
Bivalent Protein–Protein
Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage
Leukemia Interaction
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Abstract
The protein–protein interaction
between menin and mixed-lineage
leukemia 1 (MLL1) plays an important role in development of acute
leukemia with translocations of the <i>MLL1</i> gene and
in solid tumors. Here, we report the development of a new generation
of menin–MLL1 inhibitors identified by structure-based optimization
of the thienopyrimidine class of compounds. This work resulted
in compound <b>28</b> (<b>MI-1481</b>), which showed very
potent inhibition of the menin–MLL1 interaction (IC<sub>50</sub> = 3.6 nM), representing the most potent reversible menin–MLL1
inhibitor reported to date. The crystal structure of the menin-<b>28</b> complex revealed a hydrogen bond with Glu366 and hydrophobic
interactions, which contributed to strong inhibitory activity of <b>28</b>. Compound <b>28</b> also demonstrates pronounced
activity in MLL leukemia cells and <i>in vivo</i> in MLL
leukemia models. Thus, <b>28</b> is a valuable menin–MLL1
inhibitor that can be used for potential therapeutic applications
and in further studies regarding the role of menin in cancer