Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II,ACS Chemical Biology

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Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-09-24 , DOI: 10.1021/acschembio.1c00067
Laszlo Radnai _{1,

2} , Matthew Surman ₃ , Madalyn Hafenbreidel _{1,

2} , Erica J Young _{1,

2} , Rebecca F Stremel _{1,

2} , Li Lin ₁ , Bilel Bdiri ₁ , Paolo Pasetto ₃ , Xiaomin Jin ₃ , Mackenzie Geedy ₃ , Joni-Rae Partridge ₃ , Aagam Patel ₃ , Michael Conlon ₃ , James R Sellers ₄ , Michael D Cameron ₁ , Gavin Rumbaugh ₂ , Patrick R Griffin ₁ , Theodore M Kamenecka ₁ , Courtney A Miller _{1,

2}

Affiliation

Myosin IIs, actin-based motors that utilize the chemical energy of adenosine 5′-triphosphate (ATP) to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite the therapeutic potential for muscle disorders, SkMII-specific inhibitors have not been reported and characterized. Here, we present the discovery, synthesis, and characterization of “skeletostatins,” novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity 40- to 170-fold for SkMII over all other myosin II family members. In addition, the skeletostatins bear improved potency, solubility, and photostability, without cytotoxicity. Based on its optimal in vitro profile, MT-134’s in vivo tolerability, efficacy, and pharmacokinetics were determined. MT-134 was well-tolerated in mice, impaired motor performance, and had excellent exposure in muscles. Skeletostatins are useful probes for basic research and a strong starting point for drug development.

中文翻译：

用于骨骼肌球蛋白 II 体外和体内检测的选择性抑制剂的发现

肌球蛋白 II 是一种基于肌动蛋白的马达，它利用 5'-三磷酸腺苷 (ATP) 的化学能产生力量，具有作为治疗靶点的潜力。它们的重链将该家族区分为肌肉（骨骼 [SkMII]、心脏、平滑肌）和非肌肉肌球蛋白 II。尽管肌肉疾病具有治疗潜力，但尚未报道和表征 SkMII 特异性抑制剂。在这里，我们介绍了“skeletostatins”的发现、合成和表征，这是泛肌球蛋白 II 抑制剂 blebbistatin 的新型衍生物，对 SkMII 的选择性比所有其他肌球蛋白 II 家族成员高 40 到 170 倍。此外，skeletostatins 具有改进的效力、溶解度和光稳定性，而没有细胞毒性。基于其最佳的体外特性，MT-134 的体内确定了耐受性、疗效和药代动力学。MT-134 在小鼠中耐受性良好，运动性能受损，并且在肌肉中具有出色的暴露性。Skeletostatins 是基础研究的有用探针，也是药物开发的重要起点。

更新日期：2021-11-19

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