674289-55-5Relevant academic research and scientific papers
Discovery of Selective Inhibitors forIn VitroandIn VivoInterrogation of Skeletal Myosin II
Radnai, Laszlo,Surman, Matthew,Hafenbreidel, Madalyn,Young, Erica J.,Stremel, Rebecca F.,Lin, Li,Bdiri, Bilel,Pasetto, Paolo,Jin, Xiaomin,Geedy, Mackenzie,Partridge, Joni-Rae,Patel, Aagam,Conlon, Michael,Sellers, James R.,Cameron, Michael D.,Rumbaugh, Gavin,Griffin, Patrick R.,Kamenecka, Theodore M.,Miller, Courtney A.
, p. 2164 - 2173 (2021/10/12)
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 optimalin vitroprofile, MT-134’sin vivotolerability, 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.
Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties
Verhasselt, Sigrid,Roman, Bart I.,De Wever, Olivier,Van Hecke, Kristof,Van Deun, Rik,Bracke, Marc E.,Stevens, Christian V.
, p. 2104 - 2118 (2017/03/11)
In search of myosin II inhibitors with superior research tool properties, a chemical optimization campaign of the blebbistatin scaffold was conducted in this paper. (S)-Blebbistatin is the best known small-molecule inhibitor of myosin II ATPase activity. Unfortunately, as a research tool this compound has several deficiencies: it is photolabile and (photo)toxic, has low water solubility, and its (fluorescent) precipitates interfere in (fluorescence) readouts. In view of obtaining tool compounds with improved properties, both enantiomers of a series of D-ring modified polar analogs were prepared. We identified (S)-3′-hydroxyblebbistatin (S)-2 and (S)-3′-aminoblebbistatin (S)-3 as two myosin II inhibitors with a 30-fold higher water solubility than (S)-blebbistatin. These molecules furthermore do not cause interference in (fluorescence) readouts. (S)-2 and (S)-3 thus are superior alternatives to (S)-blebbistatin as research tools to study myosin II.
Improved synthesis and comparative analysis of the tool properties of new and existing D-ring modified (S)-blebbistatin analogs
Verhasselt, Sigrid,Roman, Bart I.,Bracke, Marc E.,Stevens, Christian V.
, p. 85 - 103 (2017/05/10)
(S)-Blebbistatin is a widely used research tool to study myosin II, an important regulator of many motility based diseases. Its potency is too low to be of clinical relevance, but identification of analogs with enhanced potency could deliver leads for tar
Absolute stereochemical assignment and fluorescence tuning of the small molecule tool, (-)-blebbistatin
Lucas-Lopez, Cristina,Patterson, Stephen,Blum, Till,Straight, Aaron F.,Toth, Judit,Slawin, Alexandra M. Z.,Mitchison, Timothy J.,Sellers, James R.,Westwood, Nicholas J.
, p. 1736 - 1740 (2007/10/03)
(-)-Blebbistatin (1), a recently discovered small molecule inhibitor of the ATPase activity of non-muscle myosin II has been prepared from methyl 5-methylanthranilate (6) in three steps. This flexible synthetic route has also been used to prepare a nitro
