The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Der irreversible Inhibitor Mâ 525 greift an der Meninâ MLLâ Wechselwirkung an. Die irreversible Inhibition von Menin erweist sich als vielversprechende Strategie für die Behandlung von MLLâ Leukämie, mit möglichen Vorteilen gegenüber dem Einsatz reversibler Inhibitoren.