2. Academic Validation
  3. Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-141810
    Myosin抑制剂
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