Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II

  • ACS Chem Biol. 2021 Nov 19;16(11):2164-2173. 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
Affiliations
  • 1. Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
  • 2. Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
  • 3. Albany Molecular Research Inc., 26 Corporate Circle, Albany, New York 12212, United States.
  • 4. Laboratory of Molecular Physiology, NHLBI, National Institutes of Health, 50 South Drive, B50/3529, Bethesda, Maryland 20892-8015, United States.
PMID: 34558887 DOI: 10.1021/acschembio.1c00067
Abstract

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.

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