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

Laszlo Radnai¹, Erica J Young², Carlos Kikuti³, Katalin Toth⁴, Minghai Zhou⁵, Madalyn Hafenbreidel¹, Rebecca F Stremel¹, Li Lin⁴, Paolo Pasetto⁶, Xiaomin Jin⁶, Aagam Patel⁶, Michael Conlon⁶, Sherri B Briggs¹, Leïla Heidsieck³, H Lee Sweeney⁷, James Sellers⁸, Teresa Krieger-Burke⁹, William H Martin¹⁰, Jay Sisco¹¹, Steven Young¹², Paul Pearson¹³, Gavin Rumbaugh¹⁴, Gian Luca Araldi¹⁵, Steven K Duddy¹⁶, Michael D Cameron⁴, Matthew Surman⁶, Anne Houdusse³, Patrick R Griffin⁴, Theodore M Kamenecka⁴, Courtney A Miller¹⁷

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: cmiller@scripps.edu.

PMID: 40602401
PMCID: PMC12233157 (available on 2026-07-01)
DOI: 10.1016/j.cell.2025.06.006

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

Laszlo Radnai et al. Cell. 2025.

. 2025 Aug 21;188(17):4604-4621.e15.

doi: 10.1016/j.cell.2025.06.006. Epub 2025 Jul 1.

Authors

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: cmiller@scripps.edu.

PMID: 40602401
PMCID: PMC12233157 (available on 2026-07-01)
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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Conflict of interest statement

Declaration of interests C.A.M., P.R.G., T.M.K., and E.J.Y. hold equity positions in Myosin Therapeutics, which has licensed these NMII inhibitors from UF Scripps. C.A.M., P.R.G., and T.M.K are members of the Myosin Therapeutics Board of Directors. The following patents and patent applications are related to this work: WO2019241469A1 and US63/431,234.

Update of

Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential.
Radnai L, Young EJ, Kikuti C, Hafenbreidel M, Stremel RF, Lin L, Toth K, Pasetto P, Jin X, Patel A, Conlon M, Briggs S, Heidsieck L, Sweeney HL, Sellers J, Krieger-Burke T, Martin WH, Sisco J, Young S, Pearson P, Rumbaugh G, Araldi GL, Duddy SK, Cameron MD, Surman M, Houdusse A, Griffin PR, Kamenecka TM, Miller CA. Radnai L, et al. bioRxiv [Preprint]. 2024 Oct 12:2024.10.07.617018. doi: 10.1101/2024.10.07.617018. bioRxiv. 2024. Update in: Cell. 2025 Aug 21;188(17):4604-4621.e15. doi: 10.1016/j.cell.2025.06.006. PMID: 39416074 Free PMC article. Updated. Preprint.

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

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

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