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

Laszlo Radnai; Erica J Young; Carlos Kikuti; Katalin Toth; Minghai Zhou; Madalyn Hafenbreidel; Rebecca F Stremel; Li Lin; Paolo Pasetto; Xiaomin Jin; Aagam Patel; Michael Conlon; Sherri B Briggs; Leïla Heidsieck; H Lee Sweeney; James Sellers; Teresa Krieger-Burke; William H Martin; Jay Sisco; Steven Young; Paul Pearson; Gavin Rumbaugh; Gian Luca Araldi; Steven K Duddy; Michael D Cameron; Matthew Surman; Anne Houdusse; Patrick R Griffin; Theodore M Kamenecka; Courtney A Miller

doi:10.1016/j.cell.2025.06.006

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

Cell. 2025 Jun 27:S0092-8674(25)00640-3. doi: 10.1016/j.cell.2025.06.006. Online ahead of print.

Authors

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
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.