MT125 is a brain-penetrant small-molecule inhibitor selectively targeting non-muscle myosin IIA/B (NMIIA/B) with >20-fold specificity over cardiac myosin. It demonstrates potent anti-glioblastoma activity by: (1) blocking tumor invasion and cytokinesis (inducing polyploidy), (2) disrupting mitochondrial dynamics to elevate ROS and trigger ferroptosis, and (3) sensitizing tumors to radiotherapy/kinase inhibitors via ROS-driven PDGFR/mTOR pathway activation. Subcutaneous administration achieves brain concentrations twice plasma levels (t1/2~10.5 hr) with no toxicity observed at 15× the therapeutic dose in rats. MT-125 monotherapy extends survival in GBM models, while combinations with PDGFR/PI3K inhibitors induce long-term remission (>40% mice). Its first-in-class mechanism, safety profile, and CNS bioavailability support clinical development for glioblastoma.
