Revumenib

The interaction between menin and mixed lineage leukemia fusion proteins represents a critical therapeutic target. The clinical inhibitors revumenib and ziftomenib display divergent resistance profiles against the M327I mutation, which frequently compromises revumenib efficacy while ziftomenib maintains potency. Molecular dynamics simulations of a complete __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__2 × 2 comparison matrix (WT/M327I __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__× Revumenib/Ziftomenib, three independent 500 ns replicates per system) suggest that this asymmetry arises from contrasting binding architectures. Revumenib depends on an intrinsically fragile Trp346 hydrogen bond anchor that is disrupted in multiple independent trajectories, including both M327I and WT backgrounds. Ziftomenib distributes binding energy across a redundant hydrophobic network with stable Trp346 engagement across all replicates and minimal sensitivity to position-327 perturbation. Energy decomposition shows the substantial Ile327 contribution originates from forced close-range contact, whereas the minimal Met327 contribution in ziftomenib complexes aligns with distributed network architecture. The contrasting architectures may inform the design of therapeutics with improved mutational tolerance.

Twelve independent 500 ns molecular dynamics simulations (four systems __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__× three replicates) were performed using OpenMM with AMBER ff14SB for protein and OpenFF Sage for ligands. Systems were solvated with TIP3P water. Binding free energies and per-residue contributions were estimated via MM/GBSA with the GB OBC2 implicit solvent model. Principal component analysis and dynamic cross-correlation matrices characterized conformational sampling.

Acute myeloid leukaemia (AML) remains associated with poor outcomes in relapsed or refractory disease and in molecularly defined high-risk subgroups. AML with KMT2A rearrangements (KMT2Ar) or NPM1 mutations (NPM1m) shares a dependence on the menin-KMT2A interaction, which sustains HOXA/MEIS1-driven transcription required for leukaemic maintenance. This dependence has provided the rationale for developing menin inhibitors as a targeted approach in selected AML subsets. This review summarises the mechanistic basis, clinical pharmacology, and current clinical role of menin inhibitors in AML. Revumenib, ziftomenib, bleximenib, and enzomenib are orally administered small molecules that disrupt menin-dependent transcription, induce myeloid differentiation, and have shown clinical activity in KMT2Ar and NPM1m AML. Monotherapy has produced clinically relevant remission rates in relapsed or refractory disease, and early-phase combinations with venetoclax-based therapy, hypomethylating agents, intensive chemotherapy, or FLT3 inhibitors have shown higher response rates in selected settings. Despite sharing a common target, these agents differ in dosing schedule, pharmacokinetic profile, CYP3A4-mediated drug-drug interaction potential, sensitivity to food or gastric pH, and safety profile. Differentiation syndrome and QTc prolongation are the principal toxicities requiring monitoring, although QT liability appears to vary across compounds. Acquired resistance-mediated by MEN1 binding-pocket mutations, co-occurring genomic alterations, and adaptive transcriptional or epigenetic programmes-remains a clinical limitation. Current evidence supports menin inhibition as a targeted strategy for molecularly selected AML. Ongoing studies will be important for defining optimal sequencing, combination regimens, approaches to resistance, and the role of pharmacologically informed dose optimisation in routine practice.