2. Academic Validation
  3. Development of clinically viable non-muscle myosin II small molecule inhibitors

Development of clinically viable non-muscle myosin II small molecule inhibitors

  • Cell. 2025 Aug 21;188(17):4604-4621.e15. doi: 10.1016/j.cell.2025.06.006.
Laszlo Radnai 1,  Erica J Young 2,  Carlos Kikuti 3,  Katalin Toth 4,  Minghai Zhou 5,  Madalyn Hafenbreidel 1,  Rebecca F Stremel 1,  Li Lin 4,  Paolo Pasetto 6,  Xiaomin Jin 6,  Aagam Patel 6,  Michael Conlon 6,  Sherri B Briggs 1,  Leïla Heidsieck 3,  H Lee Sweeney 7,  James Sellers 8,  Teresa Krieger-Burke 9,  William H Martin 10,  Jay Sisco 11,  Steven Young 12,  Paul Pearson 13,  Gavin Rumbaugh 14,  Gian Luca Araldi 15,  Steven K Duddy 16,  Michael D Cameron 4,  Matthew Surman 6,  Anne Houdusse 3,  Patrick R Griffin 4,  Theodore M Kamenecka 4,  Courtney A Miller 17
Affiliations

Affiliations

  • 1 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.
  • 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; Myosin Therapeutics, Jupiter, FL 33458, USA.
  • 3 Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, Paris 75248, France.
  • 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 Myosin Therapeutics, Jupiter, FL 33458, USA.
  • 6 Curia, 26 Corporate Circle, Albany, NY 12203, USA.
  • 7 Department of Pharmacology & Therapeutics, Myology Institute, University of Florida, Gainesville, FL 32610, USA.
  • 8 Laboratory of Molecular Physiology, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA.
  • 9 Pharmacology & Toxicology, In Vivo Facility, Michigan State University, East Lansing, MI 48824, USA.
  • 10 WHM Consulting, Lyme, CT 06371, USA.
  • 11 JM Sisco Pharma Consulting, Bradenton, FL 34201, USA.
  • 12 Medicinal Chemistry, BeOne Medicines, Beigene, Zhong-Guan-Cun Life Science Park, Beijing 102206, China.
  • 13 Pearson Pharma Partners, Thousand Oaks, CA 91362, USA.
  • 14 Department of Neuroscience, The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
  • 15 Avanti Biosciences, San Diego, CA 92121, USA.
  • 16 Toxicology, Certara, Ann Arbor, MI 48103, USA.
  • 17 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].
PMID: 40602401 DOI: 10.1016/j.cell.2025.06.006
Abstract

Non-muscle Myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal plasticity, has substantial therapeutic potential. However, translating this potential to in vivo use has been hampered by a lack of selective tools. The most prototypical non-selective inhibitor inactivates both NMII and cardiac muscle Myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that markedly improve tolerability by selectively targeting NMII over CMII, including MT-228 and clinical candidate MT-110. MT-228 and MT-110 have excellent properties, including high brain penetration and efficacy in preclinical models of methamphetamine use disorder (MUD), which has no current FDA-approved therapies. The structure of MT-228 bound to Myosin II provides insight into its selectivity for NMII over CMII. The broad therapeutic windows of these NMII inhibitors provide valuable tools for the scientific community and a promising clinical candidate for the treatment of MUD.

Keywords

blebbistatin; cancer; cardiac muscle myosin II; high-resolution protein-inhibitor structure; medicinal chemistry; methamphetamine; molecular motor; non-muscle myosin II; substance use disorder; therapeutic.

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