Screening of Drugs That Suppress Ste11 MAPKKK Activation in Yeast Identified a c-Abl Tyrosine Kinase Inhibitor

Takao KITAGAWA; Yuko HASHIZUME; Tatsuhiko MURAKANE; Emi KOGA; Yuki NOMURA; Yoshito KAKIHARA; Ayako FUJIEDA; Motoyuki UCHIDA; Hidetoshi TAKAHASHI; Hisashi HOSHIDA; Rinji AKADA

doi:10.1271/bbb.60610

Biochemistry & Molecular Biology Regular Papers

Screening of Drugs That Suppress Ste11 MAPKKK Activation in Yeast Identified a c-Abl Tyrosine Kinase Inhibitor

Takao KITAGAWA, Yuko HASHIZUME, Tatsuhiko MURAKANE, Emi KOGA, Yuki NOMURA, Yoshito KAKIHARA, Ayako FUJIEDA, Motoyuki UCHIDA, Hidetoshi TAKAHASHI, Hisashi HOSHIDA, Rinji AKADA

Author information

Takao KITAGAWA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Yuko HASHIZUME
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Tatsuhiko MURAKANE
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Emi KOGA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Yuki NOMURA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Yoshito KAKIHARA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Ayako FUJIEDA
Biomedical Research Laboratories, Kureha Corporation
Motoyuki UCHIDA
Biomedical Research Laboratories, Kureha Corporation
Hidetoshi TAKAHASHI
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd.
Hisashi HOSHIDA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine
Rinji AKADA
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine

Keywords: Saccharomyces cerevisiae, Ste11, drug screening, genome-wide analysis, c-Abl tyrosine kinase

JOURNAL FREE ACCESS

2007 Volume 71 Issue 3 Pages 772-782

DOI https://doi.org/10.1271/bbb.60610

View "Advance Publication" version (March 7, 2007).

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Abstract

The yeast MAPKKK Ste11 activates three MAP kinase pathways, including pheromone signaling, osmosensing, and pseudohyphal/invasive growth pathways. We identified two chemical compounds, BTB03006 and GK03225, that suppress growth defects induced by Ste11 activation in diploid yeast cells. BTB03006, but not GK03225, was found to suppress growth defects induced by both α-factor and Ste4 G_β overexpression in the pheromone signaling pathway, suggesting that GK03225 is an osmosensing pathway-specific inhibitor. We also performed genome-wide suppressor analysis for Ste11 activation, using a yeast deletion strains collection, and identified PBS2 and HOG1, and several genes associated with chaperone functions, which represent potential target proteins of the drugs screened from Ste11 activation. GK03225 possesses an Iressa-like quinazoline ring structure, and its chemical analog, 11N-078, suppresses c-Abl human tyrosine kinase activity. These results suggest that drug screening in yeast can identify human tyrosine kinase inhibitors and other drugs for human diseases.

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