Targeting the Menin– <i>KMT2A</i> Interface: Medicinal Chemistry Rules Governing Reversible, Covalent, and Degrader Inhibitors

The menin-lysine methyltransferase 2A acute leukemia (KMT2A) protein-protein interaction has emerged as a clinically validated epigenetic target in acute leukemia, following the approval of the reversible menin inhibitor Revumenib for KMT2A-rearranged and nucleophosmin 1 (NPM1)-mutant disease. This success transformed a once "undruggable" interface into a tractable binding pocket, triggering the rapid expansion of medicinal-chemistry strategies aimed at achieving deeper and more durable transcriptional reprogramming. This review analyzes the full menin-inhibitor landscape from a medicinal-chemistry perspective, integrating reversible, covalent, and degrader-oriented modalities within a unified structure-activity framework. We highlight how scaffold architecture, pocket occupancy, electrophile placement toward Cys329, and polarity tuning control binding mode, residence time, metabolic stability, resistance susceptibility, and pharmacodynamic durability. Across all chemical classes, sustained target engagement-rather than equilibrium affinity alone-emerges as the dominant determinant of antileukemic efficacy. By integrating structure-activity relationship (SAR), resistance mechanisms, safety considerations, and translational scope across oncology and metabolic indications, this review provides a roadmap for the rational design of next-generation menin inhibitors and establishes menin as a model system for modern epigenetic drug discovery.