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Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2021 Nov 19; Vol. 16 (11), pp. 2164-2173. Date of Electronic Publication: 2021 Sep 24. - Publication Year :
- 2021
-
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.
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 16
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 34558887
- Full Text :
- https://doi.org/10.1021/acschembio.1c00067