A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia.

2021 
Targeting protein-protein interactions (PPIs) by small-molecule inhibitors has become the hotbed for modern drug development. In this review we describe a new class of PPI inhibitors, which block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but it acts as an essential cofactor for MLL/KMT2A rearranged leukemias. The most promising menin-MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials to treat acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL rearranged or NPM1-mutant subtypes. These compounds are well tolerated with little or no side effects, which is remarkable given the tumor suppressor function of menin. The menin-MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution.
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