Menin is a protein that directly interacts with the Mixed Lineage Leukemia 1 (MLL1) histone methyltransferase, and this protein-protein interaction (PPI) is required for recruitment of MLL1 to target genes. Menin also binds to MLL fusion proteins and this interaction is involved in acute leukemia with MLL translocations. Accumulating evidences suggest that the menin-MLL interaction also plays an important role in solid tumors, including gliomas and prostate cancer. Therefore, small molecule inhibition of the menin- MLL interaction might represent a novel promising strategy for the treatment of various cancers. We developed small molecules that specifically bind to menin and inhibit the menin-MLL protein-protein interaction in vitro and in cells. Crystallography studies demonstrate that these compounds bind to the MLL binding site on menin and closely mimic the key MLL interactions with menin. Using structure-based design, we extensively optimized the thienopyrimidine class of menin-MLL inhibitors. Simultaneous optimization of both activity and drug-like properties was performed through systematic exploration of substituents introduced to the indole ring of these compounds. This work resulted in low nanomolar inhibitors of the menin-MLL interaction with optimized metabolic stability, selectivity and favorable pharmacokinetic profile, representing the first in vivo active chemical probes targeting this PPI. These compounds demonstrate strong effect and specific mechanism of action in MLL leukemia cells and block progression of acute leukemia in mice models of MLL leukemia. Besides, the menin-MLL inhibitors we developed showed pronounced in vitro and in vivo efficacy in metastatic castration resistant prostate cancer models, further validating their therapeutic potential. Our work provides a strong example of successful targeting of PPIs with small molecules for new potential therapeutic applications. We also demonstrate how systematic structure-based optimization of PPI inhibitors can lead to in vivo active chemical probes and possibly new therapeutics.

Development of small molecule inhibitors of the menin-MLL protein-protein interaction for cancer therapy”

251st National Meeting (2016)

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