Development of clinically viable non-muscle myosin II small molecule inhibitors PMID: 40602401

ADC Targets in Oncology

2026-04-10

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

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].

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.