MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma

  • Cell. 2025 Jun 3:S0092-8674(25)00569-0. doi: 10.1016/j.cell.2025.05.019.
Rajappa S Kenchappa  1 ,  Laszlo Radnai  2 ,  Erica J Young  2 ,  Natanael Zarco  3 ,  Li Lin  4 ,  Athanassios Dovas  5 ,  Christian T Meyer  6 ,  Ashley Haddock  3 ,  Alice Hall  2 ,  Katalin Toth  4 ,  Peter Canoll  5 ,  Naveen K H Nagaiah  3 ,  Gavin Rumbaugh  7 ,  Michael D Cameron  4 ,  Theodore M Kamenecka  4 ,  Patrick R Griffin  4 ,  Courtney A Miller  8 ,  Steven S Rosenfeld  9
Affiliations
  • 1. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected].
  • 2. Department of Molecular Medicine, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
  • 3. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 4. Department of Molecular Medicine, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
  • 5. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 6. Department of Chemical and Biological Engineering, University of Colorado, Boulder, Boulder, CO 80303, USA.
  • 7. Department of Neuroscience, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
  • 8. Department of Molecular Medicine, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA. Electronic address: [email protected].
  • 9. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected].
PMID: 40499543 DOI: 10.1016/j.cell.2025.05.019
Abstract

Glioblastoma (GBM) is the most lethal of primary brain tumors. Here, we report our studies of MT-125, a small-molecule inhibitor of non-muscle Myosin II. MT-125 has high brain penetrance and an excellent safety profile, blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR Inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR Inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.

Keywords
cancer; glioblastoma; non-muscle myosin II; oncogenic kinases; reactive oxygen species; small-molecule inhibitor; synergy; targeted therapy; toxicology.
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