Complexity of Blocking Bivalent Protein–Protein Interactions: Development of a Highly Potent Inhibitor of the Menin–Mixed-Lineage Leukemia Interaction

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 (IC₅₀ = 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