Radnai Laszlo, Young Erica J, Kikuti Carlos, Toth Katalin, Zhou Minghai, Hafenbreidel Madalyn, Stremel Rebecca F, Lin Li, Pasetto Paolo, Jin Xiaomin, Patel Aagam, Conlon Michael, Briggs Sherri B, Heidsieck Leïla, Sweeney H Lee, Sellers James, Krieger-Burke Teresa, Martin William H, Sisco Jay, Young Steven, Pearson Paul, Rumbaugh Gavin, Araldi Gian Luca, Duddy Steven K, Cameron Michael D, Surman Matthew, Houdusse Anne, Griffin Patrick R, Kamenecka Theodore M, Miller Courtney A
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.
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.
Cell. 2025 Jun 27. doi: 10.1016/j.cell.2025.06.006.
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.
非肌肉肌球蛋白II（NMII）是一种调节细胞分裂和神经元可塑性等关键过程的分子马达，具有巨大的治疗潜力。然而，由于缺乏选择性工具，将这种潜力转化为体内应用受到了阻碍。最典型的非选择性抑制剂会使NMII和心肌肌球蛋白II（CMII，心脏功能的关键调节因子）都失活。通过合理的药物设计，我们开发了一系列NMII抑制剂，这些抑制剂通过选择性地靶向NMII而非CMII，显著提高了耐受性，包括MT-228和临床候选药物MT-110。MT-228和MT-110具有优异的特性，包括高脑渗透性以及在甲基苯丙胺使用障碍（MUD）临床前模型中的疗效，目前尚无FDA批准的治疗方法。与肌球蛋白II结合的MT-228的结构揭示了其对NMII比对CMII具有选择性的原因。这些NMII抑制剂的广泛治疗窗口为科学界提供了有价值的工具，也是治疗MUD的一个有前景的临床候选药物。
