Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.
Journal article, 2011

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.

Signal Transduction

drug effects

Saccharomyces cerevisiae Proteins

Saccharomyces cerevisiae

metabolism

Enzyme Inhibitors

pharmacology

antagonists & inhibitors

Mitogen-Activated Protein Kinases

Molecular

Models

enzymology

antagonists & inhibitors

Molecular Structure

metabolism

chemistry

chemical synthesis

Author

Peter Dinér

University of Gothenburg

Jenny Veide Vilg

University of Gothenburg

Jimmy Kjellén

University of Gothenburg

Iwona Migdal

Terese Andersson

University of Gothenburg

Marinella Gebbia

Guri Giaever

Corey Nislow

Stefan Hohmann

University of Gothenburg

Robert Wysocki

Markus J. Tamás

University of Gothenburg

Morten Grötli

University of Gothenburg

PLoS ONE

1932-6203 (ISSN)

Vol. 6 5 e20012-

Subject Categories

Biochemistry and Molecular Biology

Medicinal Chemistry

Organic Chemistry

DOI

10.1371/journal.pone.0020012

PubMed

21655328

More information

Latest update

4/18/2018