2. Academic Validation
  3. MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma

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

Affiliations

  • 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: kenchappa.rajappa@mayo.edu.
  • 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: cmiller@scripps.edu.
  • 9 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: rosenfeld.steven@mayo.edu.
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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