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Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.

Dinér P, Veide Vilg J, Kjellén J, Migdal I, Andersson T, Gebbia M, Giaever G, Nislow C, Hohmann S, Wysocki R, Tamás MJ, Grøtli M - PLoS ONE (2011)

Bottom Line: These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo.Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress.Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Chemistry, University of Gothenburg, Göteborg, Sweden.

ABSTRACT
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

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p38 kinase inhibitors.SB 203580 is a pyridinyl imidazole inhibitor of p38 MAPK that                        specifically blocks its kinase activity and is widely used as a research                        tool. Compounds 1a–1e were recently                        described as p38α inhibitors.
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pone-0020012-g001: p38 kinase inhibitors.SB 203580 is a pyridinyl imidazole inhibitor of p38 MAPK that specifically blocks its kinase activity and is widely used as a research tool. Compounds 1a–1e were recently described as p38α inhibitors.

Mentions: The MAPK p38 is the mammalian ortholog of yeast Hog1 and is extensively studied due to its involvement in chronic inflammatory diseases [21]. p38 is also activated by As(III) [22] and triggers cell cycle arrest, differentiation, or mitochondrial apoptotic cell death [23], [24]. One class of selective p38 inhibitors is the pyridinylimidazole-based compounds (SB) [25], [26]. Several of these compounds are highly potent and inhibit p38 at nanomolar concentrations (Figure 1). However, these inhibitors cannot be used for in vivo inhibition of Hog1 since they do not accumulate in yeast cells (see Uptake of inhibitors by yeast cells). Recently, we took advantage of the structural similarities between 4- and 5-substituted 1,2,3-triazoles and pyridinylimidazole-based inhibitors in the design of new inhibitors of p38, which prompted us to explore the use of triazoles as potential Hog1 inhibitors [27]. Herein, we report the design, synthesis, and biological evaluation of potent and selective 4- and 5-substituted 1,2,3-triazoles as wtHog1 inhibitors. Using two of these novel inhibitors, we demonstrate that Hog1 controls the exit from As(III)-induced cell cycle arrest.


Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.

Dinér P, Veide Vilg J, Kjellén J, Migdal I, Andersson T, Gebbia M, Giaever G, Nislow C, Hohmann S, Wysocki R, Tamás MJ, Grøtli M - PLoS ONE (2011)

p38 kinase inhibitors.SB 203580 is a pyridinyl imidazole inhibitor of p38 MAPK that                        specifically blocks its kinase activity and is widely used as a research                        tool. Compounds 1a–1e were recently                        described as p38α inhibitors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104989&req=5

pone-0020012-g001: p38 kinase inhibitors.SB 203580 is a pyridinyl imidazole inhibitor of p38 MAPK that specifically blocks its kinase activity and is widely used as a research tool. Compounds 1a–1e were recently described as p38α inhibitors.
Mentions: The MAPK p38 is the mammalian ortholog of yeast Hog1 and is extensively studied due to its involvement in chronic inflammatory diseases [21]. p38 is also activated by As(III) [22] and triggers cell cycle arrest, differentiation, or mitochondrial apoptotic cell death [23], [24]. One class of selective p38 inhibitors is the pyridinylimidazole-based compounds (SB) [25], [26]. Several of these compounds are highly potent and inhibit p38 at nanomolar concentrations (Figure 1). However, these inhibitors cannot be used for in vivo inhibition of Hog1 since they do not accumulate in yeast cells (see Uptake of inhibitors by yeast cells). Recently, we took advantage of the structural similarities between 4- and 5-substituted 1,2,3-triazoles and pyridinylimidazole-based inhibitors in the design of new inhibitors of p38, which prompted us to explore the use of triazoles as potential Hog1 inhibitors [27]. Herein, we report the design, synthesis, and biological evaluation of potent and selective 4- and 5-substituted 1,2,3-triazoles as wtHog1 inhibitors. Using two of these novel inhibitors, we demonstrate that Hog1 controls the exit from As(III)-induced cell cycle arrest.

Bottom Line: These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo.Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress.Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Chemistry, University of Gothenburg, Göteborg, Sweden.

ABSTRACT
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.

Show MeSH
Related in: MedlinePlus