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The protein–protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) protein plays a critical role in a subset of acute leukemia, including leukemias with MLL1 translocations or mutations in the nucleophosmin (NPM1) gene, providing an opportunity for therapeutic intervention. Indeed, multiple small molecule inhibitors directly targeting menin to block its interactions with MLL1 were reported within the last decade. These compounds demonstrate pronounced anti-leukemic activity in pre-clinical models of MLL1-rearranged and NPM1-mutated leukemia, resulting in clinical translation of several of these compounds to acute leukemia patients. Discovery, development and early clinical data for the most promising menin inhibitors are discussed in this chapter.

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