MT-125 as a promising targeted therapy for glioblastoma through NMII inhibition and ROS-mediated apoptosis

In a 2025 Cell study, Kenchappa et al. evaluated MT-125, a selective dual inhibitor of non-muscle myosin IIA/B (NMIIA/B) derived from the pan-myosin II inhibitor blebbistatin, as a therapeutic agent for glioblastoma (GBM). Mechanistically, MT-125 inhibits NMIIA/B to impair mitochondrial fission, causing mitochondrial elongation and elevated reactive oxygen species (ROS). ROS induce ferroptosis via lipid peroxidation and DNA damage (e.g., γH2AX upregulation) through poly(ADP-ribose) polymerase cleavage. Additionally, ROS activate platelet-derived growth factor receptor (PDGFR) signaling, triggering RAS–RAF–MEK–ERK1/2 and PI3K–AKT–mTOR cascades; mammalian target of rapamycin (mTOR) further amplifies ROS production, forming a pro-apoptotic positive feedback loop. In in vitro assays and genetically engineered mouse models (GEMMs) of GBM, MT-125 significantly reduced tumor proliferation (via multinucleation) and invasion, prolonged survival, and exhibited favorable drug properties, including high brain permeability and a safety profile characterized by minimal toxicity to normal cells/organs, and no sex-based weight differences. Combination therapies (MT-125 with Sunitinib, phosphatidylinositol 3-kinase [PI3K]/mTOR inhibitors, or radiotherapy) outperformed monotherapies in suppressing tumor growth and enhancing apoptosis. This study identifies NMII as a key GBM target and highlights MT-125’s strong therapeutic potential, though further research is needed to assess its risk of inducing chromosomal instability/aneuploidy in normal cells.