| Title: | Screening of drugs that suppress Ste11 MAPKKK activation in yeast identified a c-Abl tyrosine kinase inhibitor |
| Author(s): | Kitagawa T; Hashizume Y; Murakane T; Koga E; Nomura Y; Kakihara Y; Fujieda A; Uchida M; Takahashi H; Hoshida H; Akada R; |
| Address: | "Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine, Ube, Japan" |
| Journal Title: | Biosci Biotechnol Biochem |
| ISSN/ISBN: | 0916-8451 (Print) 0916-8451 (Linking) |
| 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 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" |
| Keywords: | "Diploidy Drug Evaluation, Preclinical Enzyme Activation Genome, Fungal Humans MAP Kinase Kinase Kinases/*metabolism Mitogen-Activated Protein Kinases/*metabolism Pheromones/*physiology Phosphorylation Protein Kinase Inhibitors/*pharmacology Proto-Oncogene;" |
| Notes: | "MedlineKitagawa, Takao Hashizume, Yuko Murakane, Tatsuhiko Koga, Emi Nomura, Yuki Kakihara, Yoshito Fujieda, Ayako Uchida, Motoyuki Takahashi, Hidetoshi Hoshida, Hisashi Akada, Rinji eng Research Support, Non-U.S. Gov't England 2007/03/08 Biosci Biotechnol Biochem. 2007 Mar; 71(3):772-82. doi: 10.1271/bbb.60610. Epub 2007 Mar 7" |
