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Targeting protein‐protein interactions (PPIs) with small‐molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the  MEN1  tumor suppressor, but 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 for treating 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 few 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.

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