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. 2025 Aug 21;188(17):4622-4639.e19.
doi: 10.1016/j.cell.2025.05.019. Epub 2025 Jun 10.

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

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

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

Rajappa S Kenchappa et al. Cell. .

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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Conflict of interest statement

Declaration of interests E.J.Y., P.R.G., T.M.K., C.A.M., and S.S.R. have an equity interest in Myosin Therapeutics. C.T.M. is a co-founder and partial equity holder in Duet BioSystems. S.S.R. and M.T. are members of the External Scientific Advisory Board of Myosin Therapeutics-125 and are protected by Patent #US63/431,234, “Combination Therapy for the Treatment of Glioblastoma,” with the US Patent Office.

Update of

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