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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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Retro-synthetic analysis of the target compounds.
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pone-0020012-g003: Retro-synthetic analysis of the target compounds.

Mentions: Previously, we had recognized the Cu(I)-catalyzed azide-alkyne 1,3-dipolar [2+3]-cycloaddition reaction as the key step in forming five-membered 4- and 5-substituted 1,2,3-triazoles, which can easily be coupled via a Suzuki coupling to yield compounds that have been evaluated as p38α inhibitors (compounds 1a–1e; see Figure 1) [27]. By the use of the bifunctional 2-chloropyridine boronic acid in the Suzuki coupling, the reaction sequence can be extended via a Hartwig-Buchwald C-N bond coupling, yielding the target compounds containing the amine substituent in the 2-position of the pyridine ring (Figure 3) [31].


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)

Retro-synthetic analysis of the target compounds.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020012-g003: Retro-synthetic analysis of the target compounds.
Mentions: Previously, we had recognized the Cu(I)-catalyzed azide-alkyne 1,3-dipolar [2+3]-cycloaddition reaction as the key step in forming five-membered 4- and 5-substituted 1,2,3-triazoles, which can easily be coupled via a Suzuki coupling to yield compounds that have been evaluated as p38α inhibitors (compounds 1a–1e; see Figure 1) [27]. By the use of the bifunctional 2-chloropyridine boronic acid in the Suzuki coupling, the reaction sequence can be extended via a Hartwig-Buchwald C-N bond coupling, yielding the target compounds containing the amine substituent in the 2-position of the pyridine ring (Figure 3) [31].

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