Screening of drugs that suppress Ste11 MAPKKK activation in yeast identified a c-Abl tyrosine kinase inhibitor.
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 alpha-factor and Ste4 G(beta) 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.
Kitagawa
Takao
T
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Hashizume
Yuko
Y
Murakane
Tatsuhiko
T
Koga
Emi
E
Nomura
Yuki
Y
Kakihara
Yoshito
Y
Fujieda
Ayako
A
Uchida
Motoyuki
M
Takahashi
Hidetoshi
H
Hoshida
Hisashi
H
Akada
Rinji
R
D004171:Diploidy; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D016681:Genome, Fungal; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010675:Pheromones / Q000502:physiology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction / Q000502:physiology; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism*
D010675:Pheromones; D047428:Protein Kinase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D016315:Proto-Oncogene Proteins c-abl; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C067018:Ste11 protein, S cerevisiae