临床可行的非肌球蛋白II小分子抑制剂的开发，这一成果由斯克里普斯研究所Courtney A. Miller课题组经过不懈努力而取得。这一研究成果发表在2025年7月1日出版的国际学术期刊《细胞》上。
通过合理的药物设计，该团队开发了一系列NMII抑制剂，通过选择性靶向NMII而不是CMII，显著提高耐受性，包括MT-228和临床候选MT-110。MT-228和MT-110在甲基苯丙胺主题障碍（MUD）的临床前模型中具有优异的性能，包括高脑穿透性和有效性，目前尚无FDA批准的治疗方法。结合肌球蛋白II的MT-228的结构提供了其对NMII而不是CMII的选择性的见解。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，并为治疗MUD提供了有前途的临床候选药物。
研究人员表示，非细胞肌球蛋白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主题受到阻碍。最典型的非选择性抑制剂使NMII和心肌肌球蛋白II （CMII）失活，CMII是心脏功能的关键调节因子。
附：英文原文
Title: Development of clinically viable non-muscle myosin II small molecule inhibitors
Author: 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, Lela 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
Issue&Volume: 2025-07-01
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.
DOI: 10.1016/j.cell.2025.06.006
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00640-3